Diagnostic procedures using direct injection of gaseous hyperpolarized 129Xe and associated systems and products

ABSTRACT

A method of screening for pulmonary embolism uses gaseous phase polarized  129 Xe which is injected directly into the vasculature of a subject. The gaseous  129 Xe can be delivered in a controlled manner such that the gas substantially dissolves into the vasculature proximate to the injection site. Alternatively, the gas can be injected such that it remains as a gas in the bloodstream for a period of time (such as about 8-29 seconds). The injectable formulation of polarized  129 Xe gas is presented in small quantities of (preferably isotopically enriched) hyperpolarized  129 Xe and can provide high-quality vasculature MRI images or NMR spectroscopic signals with clinically useful signal resolution or intensity. One method injects the polarized  129 Xe as a gas into a vein and also directs another quantity of polarized gas into the subject via inhalation. In this embodiment, the perfusion uptake allows arterial signal information and the injection (venous side) allows venous signal information. The dual delivery is used to generate a combined introduction path with a more complete image signal of both the arterial and venous side of the pulmonary vasculature. In this NMR imaging method, the pulmonary embolism screening method can use the same NMR chest coil for the excitation and detection of the  129 Xe signals. The direct injection of small quantities of gas at particular sites along the vasculature targets specific target regions to provide increased signal intensity NMR images. The disclosure also includes related methods directed to other diagnostic vasculature regions physiological and conditions. Associated delivery and dispensing systems and methods, containers, and quantitative formulations of the polarized gas are also described.

RELATED APPLICATIONS

[0001] This application claims the benefit of priority from U.S.Provisional Application Serial No. 60/189,072 filed Mar. 13, 2000, thecontents of which are hereby incorporated by reference as if recited infull herein.

FIELD OF THE INVENTION

[0002] The present invention relates generally to magnetic resonanceimaging (“MRI”) and spectroscopy methods, and more particularly to theuse of hyperpolarized ¹²⁹Xe in MRI and spectroscopy.

BACKGROUND OF THE INVENTION

[0003] MRI using hyperpolarized noble gases has been demonstrated as aviable imaging modality. See e.g., U.S. Pat. No. 5,545,396 to Albert etal. The contents of this patent are hereby incorporated by reference asif recited in full herein. Albert et al. proposed several techniques ofintroducing the hyperpolarized gas (either alone or in combination withanother substance) to a subject, such as via direct injection,intravenous injection, and inhalation. See also Biological magneticresonance imaging using laser-polarized ¹²⁹Xe, 370 Nature, pp. 199-201(Jul. 21, 1994). Other researchers have since obtained relativelyhigh-quality images of the lung using pulmonary ventilation of the lungwith both hyperpolarized ³He and ¹²⁹Xe. See J. R. MacFall, H. C.Charles, R. D. Black, H. Middleton, J. Swartz, B. Saam, B. Driehuys, C.Erickson, W. Happer, G. Cates, G. A. Johnson, and C. E. Ravin, “Humanlung air spaces: Potential for MR imaging with hyperpolarized He-3, ”Radiology 200, 553-558 (1996); and Mugler et al., MR Imaging andspectroscopy using hyperpolarized ¹²⁹Xe gas: Preliminary human results,37 Mag. Res. Med., pp. 809-815 (1997). See also E. E. de Lange, J. P.Mugler, J. R. Brookeman, J. Knight-Scott, J. Truwit, C. D. Teates, T. M.Daniel, P. L. Bogorad, and G. D. Cates, “Lung Airspaces: MR ImagingEvaluation with Hyperpolarized Helium-3 Gas, ” Radiology 210,851-857(1999); L. F. Donnelly, J. R. MacFall, H. P. McAdams, J. M.Majure, J. Smith, D. P. Frush, P. Bogorad, H. C. Charles, and C. E.Ravin, “Cystic Fibrosis: Combined Hyperpolarized 3He-enhanced andConventional Proton MR Imaging in the Lung—Preliminary Observations,”Radiology 212 (September 1999), 885-889 (1999); H. P. McAdams, S. M.Palmer, L. F. Donnelly, H. C. Charles, V. F. Tapson, and J. R. MacFall,“Hyperpolarized 3He-Enhanced MR Imaging of Lung Transplant Recipients:Preliminary Results,” AJR 173, 955-959 (1999).

[0004] In addition, due to the high solubility of ¹²⁹Xe in blood andtissues, vascular and tissue imaging using inhaled hyperpolarized ¹²⁹Xehas also been proposed. Generally described, during inhalation delivery,a quantity of hyperpolarized ¹²⁹Xe is inhaled by a subject (a subjectbreathes in the ¹²⁹Xe gas) and the subject then holds his or her breathfor a short period of time, i.e., a “breath-hold” delivery. This inhaled¹²⁹Xe gas volume then exits the lung space and is generally taken up bythe pulmonary vessels and associated blood or pulmonary vasculature at arate of approximately 0.3% per second. For example, for an inhaledquantity of about 1 liter of hyperpolarized ¹²⁹Xe, an estimated uptakeis about 3 cubic centimeters per second or a total quantity of about 40cubic centimeters of ¹²⁹Xe over about a 15 second breath-hold period.Accordingly, it has been noted that such uptake can be used to generateimages of pulmonary vasculature or even organ systems more distant fromthe lungs. See co-pending and co-assigned U.S. patent application Ser.No. 09/271,476 to Driehuys et al, entitled Methods for Imaging Pulmonaryand Cardiac Vasculature and Evaluating Blood Flow Using DissolvedPolarized ¹²⁹Xe. Although primarily directed to inhalation delivery,this application also proposes injection of ¹²⁹Xe to replaceconventional radioactive tracers in perfusion imaging methods. Thecontents of this application are hereby incorporated by reference as ifrecited in full herein.

[0005] Many researchers are also interested in the possibility of usinginhaled ¹²⁹Xe for imaging white matter perfusion in the brain, renalperfusion, and the like. While the inhaled delivery ¹²⁹Xe methods aresuitable, and indeed, preferable, for many MRI applications for severalreasons, such as the non-invasive characteristics attendant with such adelivery to a human subject, it may not be the most efficient method todeliver a sufficiently large dose to more distant (away from thepulmonary vasculature which is proximate to the lungs) target areas ofinterest. In addition, due to the dilution of the inhaled ¹²⁸Xe alongthe perfusion delivery path, relatively large quantities of thehyperpolarized ¹²⁹Xe are typically inhaled in order to deliver a smallfraction of the gas to the more distal target sites or organ systems.For example, the brain typically receives only about 13% of the totalblood flow in the human body. Thus, the estimated 40 cubic centimeterquantity of hyperpolarized ¹²⁹Xe taken up into the pulmonary vesselsfrom the 1-liter inhalation dose can be reduced to only about 5 cubiccentimeters by the time it reaches the brain.

[0006] Further, the hyperpolarized state of the gas is sensitive and candecay relatively quickly due to a number of relaxation mechanisms.Indeed, the relaxation time (generally represented by a decay constant“T₁”) of the ¹²⁹Xe in the blood, absent other external depolarizingfactors, is estimated at T₁=4.0 seconds for venous blood and T₁=6.4s forarterial blood at a magnetic field strength of about 1.5 Tesla. SeeWolber et al., Spin-lattice relaxation of laser-polarized xenon in humanblood, 96 Proc. Natl. Acad. Sci. USA, pp. 3664-3669 (March 1999). (Themore oxygenated arterial blood provides increased polarization life overthe relatively de-oxygenated venous blood). Therefore, for about a 5second transit time (the time estimate for the uptaken hyperpolarized¹²⁹Xe to travel to the brain from the pulmonary vessels), the ¹²⁹Xepolarization is reduced to about 37% of its original value. In addition,the relaxation time of the polarized ¹²⁹Xe in the lung itself istypically about 20-25 seconds due to the presence of paramagneticoxygen. Accordingly, ¹²⁹Xe taken up in the latter portion of thebreath-hold cycle can decay to have only about 50% of the startingpolarization (the polarization level at the initial portion of thebreath hold cycle). Thus, generally stated, the average polarization of¹²⁹Xe entering the pulmonary blood can be estimated to be at about 75%of the starting inhaled polarization value. Taking these effects intoaccount, the delivery to the brain of the inhaled ¹²⁹Xe can be estimatedas about 1.4 cubic centimeters of the inhaled one-liter dose of ¹²⁹Xepolarized to the same level as the inhaled gas (0.75×0.37×5 cc's). Thisdilution reduces delivery efficiency, i.e., for remote target areas(such as the brain), the quantity of delivered ¹²⁹Xe is typicallyseverely reduced to only about 0.14% of the inhaled ¹²⁹Xe. Nonetheless,at least one researcher has made coarse images of ¹²⁹Xe in rat brains,but this inhalation administration delivery required large quantities of¹²⁹Xe to be inhaled over a relatively long period of time. See Swansonet al., Brain MRI with laser-polarized xenon in human blood, 38 Mag.Reson. Med., pp. 695-698 (1997). Unfortunately, the extended inhalationtime period and/or associated large quantity dosage of the gas may notbe desirable for certain clinical applications.

[0007] In an alternative delivery mode, Bifone et al. proposes the useof injectable formulations to deliver hyperpolarized ¹²⁹ Xe to regionsof interest. Bifone et al., NMR of laser polarized xenon in human blood,93 Proc. Natl. Acad. Sci. USA No. 23, pp. 12932-12936 (1996). Albert etal., supra, also describes such formulations. As described by Bifone etal., the injectable formulation consists of a biocompatible fluid inwhich hyperpolarized ¹²⁹Xe is dissolved. Such formulations can then beinjected intravenously to deliver hyperpolarized ¹²⁹Xe. For fluidinjection, the formulation is described as preferably formed such thatthe biocompatible fluid has a high solubility for xenon while alsoproviding a relatively long ¹²⁹Xe relaxation time. Examples ofparticular suggested biocompatible fluids include saline, lipidemulsions, and perfluorocarbon emulsions. Several researchers have shownimages of fluid injectable formulations. For example, Goodson et al.have shown images of ¹²⁹Xe dissolved in saline and injected into thehind leg of a rat. Goodson et al., In vivo NMR and MRI Using InjectionDelivery of Laser-Polarized Xenon, 94 Proc. Natl. Acad. Sci. USA, pp.14725-14729 (1997). Moeller et al. have also recently demonstratedvenous angiography with hyperpolarized ¹²⁹Xe dissolved in Intralipid®solution. Moeller et. al., Magnetic Resonance Angiography withHyperpolarized 129Xe Dissolved in Lipid Emulsion, 41 Mag. Res. Med. No.5, pp. 1058-1064 (1999). The Intralipid® formulation purportedly has axenon-Otswald solubility of about 0.6 and a ¹²⁹Xe relaxation time of 25seconds in a magnetic field strength of 2.0 Tesla. In addition, Wolberet al, have also recently demonstrated PFOB (perfluorooctyl bromide)emulsions which allegedly have increased transverse relaxation times andhave purportedly provided improved imaging results. Wolber et al.,Perfluorocarbon Emulsions as Intravenous Delivery Media forHyperpolarized Xenon, 41 Mag. Res. Med., pp. 442-449 (1999). In yetanother injection technique, Chawla et al., have proposed the use ofhyperpolarized ³He microbubbles suspended in a hexabrix solution toperform angiography on rats. Chawla et al., In Vivo Magnetic ResonanceVascular Imaging Using Laser-Polarized 3He Microbubbles, 95 Proc. Natl.Acad. Sci. USA, pp. 10832-10835 (1998).

[0008] Unfortunately, many injectable formulations can be undulysusceptible to handling and processing variables which can negativelyimpact the injectable formulation's commercial viability and/or clinicalapplication. For example, the relatively short (and potentiallymagnetic-field dependent) relaxation time of the ¹²⁹Xe in the injectablesolutions can require that the ¹²⁹Xe gas be dissolved into thebiocompatible fluid relatively quickly and then subsequently rapidlyinjected to reduce the polarization loss of the formulation prior toinjection. In addition, it may be difficult to predict the dissolutionefficiency in a manner which can provide a reliable xenon dissolutionconcentration. Unreliable concentrations can, unfortunately, yieldwidely varying signal intensities, dose to dose. Further, because of thetypically relatively quick decay associated with these formulations, acareful measurement of the final ¹²⁹Xe polarization just prior toinjection to determine the post dissolution polarization may not bepossible. Still further, because the ¹²⁹Xe is dissolved in abiocompatible fluid, sensitivity to the local in vivo environment suchas blood oxygenation, tissue type, and the like, may be muted, reduced,or even non-existent. The use of such fluids or carrier agents todeliver ¹²⁹Xe to selected tissues or organs can also be difficultbecause of the high solubility of ¹²⁹Xe in the fluid compared to thetissues (its preferred affinity being to remain in the fluid rather thanto migrate into the selected or targeted tissues).

[0009] In view of the foregoing, and despite the present efforts, therecontinues to be a need to improve the methods, products, and systemsused to deliver hyperpolarized ¹²⁹Xe gas to a target in vivo imagingregion of interest.

OBJECTS AND SUMMARY OF THE INVENTION

[0010] It is therefore an object of the present invention to formulateand deliver ¹²⁹Xe in vivo in a manner which allows for high-qualitymammalian tissue, organ, vascular, and/or angiographic MRI images usinghyperpolarized gaseous ¹²⁹Xe.

[0011] It is another object of the present invention to provide a methodof using reduced quantities of hyperpolarized gas while providingincreased MRI image signal resolution.

[0012] It is an additional object of the present invention to providemethods for obtaining improved quality NMR signals and/or MRI images ofboth the arterial and venous portions of the human vasculature and/ororgans and/or systems using hyperpolarized ¹²⁹Xe.

[0013] It is a further object of the present invention to provideappropriate (bolus) sized containers and associated delivery systems,apparatus, and methods which can reduce the depolarization of thehyperpolarized ¹²⁹Xe gas prior to and during delivery and can, thus,yield a clinically useful T₁.

[0014] It is another object of the present invention to introduce asufficient quantity of hyperpolarized ¹²⁹Xe gas into the vasculature ina minimally intrusive manner to obtain MR spectroscopic signal and/or invivo images.

[0015] It is yet another object of the present invention to facilitatethe dissipation or dispersion of bubbles which may be injected into asubject.

[0016] It is an additional object of the present invention to provideimaging methods which may be able to screen for the presence ofpulmonary emboli.

[0017] It is still another object of the invention to formulate ¹²⁹Xe asa pharmaceutical grade injectable formulation which can be monitored forpolarization efficacy just prior to use with reduced decaying effectthereon.

[0018] It is another object of the present invention to provideNMR-based diagnostic capability of vasculature (arterial and/or venousor organ) circulation related defects or emboli in a minimally ornon-invasive and effective manner.

[0019] It is yet another object of the present invention to provide adiagnostic tool for the evaluation of pharmaceutical effectiveness ondrugs directed to target regions or functions.

[0020] It is an additional object of the present invention to provide invivo diagnostic information regarding the cancerous condition of a solidmass.

[0021] It is another object of the present invention to prepare gascontacting surfaces and containers in a manner which reduces the amountof depolarizing oxygen therein while also employing purge gas which issuitable for injection.

[0022] It is still an additional object of the present invention toprovide a way to optimize capillary length for improved polarizationlife in containers configured to hold polarized noble gases such as¹²⁹Xe and/or ³He.

[0023] These and other objects of the present invention are provided bydirectly injecting in vivo a predetermined quantity of hyperpolarized¹²⁹Xe in gaseous phase to obtain MR based spectroscopic signal or imagesregarding a target site in the mammalian vasculature (or target organ,tissue, or region). The present invention also includes delivery anddispensing methods, systems, and product formulations, as well asadministration rates which may correspond to the use or injection site.In addition, the present invention provides polarization monitoring ofthe hyperpolarized gaseous ¹²⁹Xe which is formulated for directinjection in vivo into the vasculature for MR imaging and spectroscopicanalysis.

[0024] In particular, a first aspect of the present invention isdirected toward the detection or screening for the presence of apulmonary embolism. The method includes the step of positioning asubject having a pulmonary region and a blood circulation path includingveins and arteries in a NMR system. The subject's pulmonary region haspulmonary veins and pulmonary arteries and associated vasculaturedefining a pulmonary portion of the circulation path. A quantity ofpolarized gaseous ¹²⁹Xe is injected directly into at least one vein ofthe subject. NMR signal data associated with the polarized ¹²⁹Xe in thepulmonary region of the subject is obtained. The signal data includesinformation corresponding to the polarized gas introduced in theinjecting step. An MRI image is generated having spatially coded visualrepresentation of the NMR signal data. The presence of at least onecondition of blockage, restriction, abnormality, and substantiallyunobstructed free passage of the pulmonary circulation path isidentified.

[0025] In one embodiment, the quantity of venous injected gaseous ¹²⁹Xeis less than about 100 cubic centimeters while quantity of arterialinjected gaseous ¹²⁹Xe is less than about 14-20 cc's.

[0026] In another embodiment, in order facilitate bubble dissipationwhich may be associated with the injection of the ¹²⁹Xe gas within thesubject, a quantity of liquid surfactant can be introduced in vivotemporally and spatially proximate to the gas injection (or concurrentlyat a location proximate to the gas injection) site. The injectionpressure and/or the rate of injection can also be substantiallycontrolled to thereby control the delivery rate of the polarized gaseous¹²⁹Xe into the injection site typically to about 1-3 cc/s or less forvenous entry. The gas injection may be performed in a manner whichreduces the bubble size associated with the injected gas to preferablyto less than about 5-10 μm in diameter for certain embodiments(particularly for arterial injections) and less than about 75-150 μm indiameter for venous injections.

[0027] In one embodiment, a second quantity of a polarized gas isintroduced to a subject during the same imaging session. That is, thefirst quantity is injected and an associated first image or signalacquisition can be obtained, and a second delivery and a second data orsignal acquisition or image associated with the second quantity can beobtained. For example, the second delivery can be via inhalation of ahyperpolarized gas (either ³He or ¹²⁹Xe, although for system equipmentand coil tuning reasons, ¹²⁹Xe gas is preferred) and the signal/imagecan be obtained after a short lapsed time period from the firstsignal/image (a time sufficient to clear traces of the polarizedinjected xenon from the target area). Additionally, or alternatively,the inhalation dose can be delivered prior to the injection of thepolarized gas. Alternatively, concurrent delivery of the injection andinhalation doses may be used. It is anticipated that this may help withco-registration between the two images and may reduce image artifacts.Of course, the second delivery can be another injectable dose of ¹²⁹Xegas, or an injection of a hyperpolarized gas product in liquid form(such as dissolved in a carrier liquid).

[0028] Another aspect of the present invention is directed toward amethod of obtaining MRI-based medical images. The method includesinjecting directly into an injection site of a subject a first quantityof polarized ¹²⁹Xe in gaseous form and delivering a second quantity ofpolarized gas product to the subject within the same imaging session.The second delivery can be performed in a number of ways and with anumber of polarized noble gas product formulations. For example,inhalation of a polarized noble gas mixture (such as described for theembodiment above) or another injection (either of the ¹²⁹Xe gas directlyor of a polarized noble gas product otherwise formulated such as in acarrier or liquid based injection formulation) at a point in time whichis proximate to the injecting step. The second quantity is larger thanthe first (injected) quantity. An MRI image is then generatedcorresponding to the signal data acquisition obtained via NMR excitationof the first and second quantities of polarized gas introduced in saidinjecting and delivering steps.

[0029] In certain embodiments, the injecting step injection site is asite associated with the venous vasculature (such as a vein). In oneembodiment, the delivering step is carried out by administering twoseparate polarized gas based doses. That is, the delivery step may beperformed by injecting to second site in an artery and by inhaling aquantity of hyperpolarized gas. The second site or arterial injectionquantity can be in fluid or gas formulation. Thus, the inhalation baseddelivering step introduces the polarized gas via inhalation and theinhaled gas is subsequently directed into pulmonary arterial vasculaturevia perfusion uptake.

[0030] In another embodiment, the NMR signal data associated with boththe injecting and delivering steps is processed in a manner whichdistinguishes NMR signal information corresponding to gas versusdissolved gas signal information in the MRI image generating step.Alternatively, the MRI image-generating step is performed at a lowmagnetic field strength, and the NMR signal data is processed in amanner which combines or does not substantially distinguish between NMRsignal data associated with excitation of the hyperpolarized gas whetherin the gas phase or the dissolved phase (the peaks associated with thepolarized gas in the red blood cells and plasma in the blood overlap).

[0031] An additional aspect of the present invention is directed to amethod of obtaining diagnostic images of the cranial region. The methodincludes the steps of injecting less than about 5 cc's (preferably about1-2 cc's) of ¹²⁹Xe polarized gas into an injection site in a carotidartery and dissolving the polarized ¹²⁹Xe gas into the vasculatureproximate to the injection site. An NMR image is generated having signalintensity associated with the NMR excitation of the dissolved ¹²⁹Xe. Thesignal can be associated with the ¹²⁹Xe in one or more of the blood,grey matter, CSP, or white matter (to provide information correspondingto white matter perfusion typical of desired neurological assessments).The excitation or response signal can be processed in a manner whichallows the correlation to a particular region of interest, such as, forexample, highlighting differences in chemical shift, T₂*, T₁, and thelike as will be appreciated by one of skill in the art. The method caninclude, inter alia, the step of introducing, in vivo, a surfactant tofacilitate bubble dissipation proximate to the injection site

[0032] In one embodiment, the injecting step is performed at a(controlled) rate and/or pressure sufficient to facilitate thedissolution of the gas in the vasculature proximate to the injectionsite and/or in a manner which reduces the size of bubbles introducedtherewith corresponding to the selected injection site (preferably toform smaller size bubbles and smaller quantities of gas for arterialinjections). An injection head with multiple orifices sized with adiameter of between about 1 nm-50 μm, and typically between about0.01-10 μm can be used and the gas may be mixed in situ with anemulsifier prior to delivery to facilitate a fine dispersion of gas intothe body of the subject.

[0033] Another aspect of the present invention is directed toward amethod of obtaining an MR image or NMR spectral data. The methodincludes injecting less than about 100 cc's of hyperpolarized gas invivo into an injection site associated with the vasculature of amammalian subject. An NMR image or spectral data is then generatedcorresponding to the injected quantity of hyperpolarized ¹²⁹Xe gas.

[0034] In one embodiment the method includes the step of administeringthe injection such that it remains substantially undissolved within thebloodstream for a period of time and such that it exhibits a T₁ in thebloodstream of at least eight seconds. Alternatively, the method canadminister the injection such that is employs an introduction rateselected so that the gas is dissolved (at least partially) into thevasculature proximate to the injection site and/or to reduce the size ofbubbles associated with the injection.

[0035] In certain embodiments, the injection is performed by injectingthe hyperpolarized ¹²⁹Xe into at least one predetermined injection sitesuch as in an arm, leg, or at other externally accessible or viableinjection locations. For example, the injection site can be chosen fromthe group consisting of a carotid artery, a pulmonary artery, a renalartery, a hepatic artery, and a renal artery or the group consisting ofa vein located in the arm (such as the central vein or peripheral vein),a jugular vein, a pulmonary vein, a hepatic vein, and a renal vein. Inanother preferred embodiment, the injecting step is performed byinjecting the hyperpolarized ¹²⁹Xe into at least two different injectionsites, preferably the injection sites corresponding to a vein or arterywhich is externally accessible via injection of an IV or syringe needlesuch as in an arm, leg, or at other torso or other feasible locations.

[0036] The injection dose can be contained in a single-dose sizedcontainer. For arterial injections, the dose container can be sized andconfigured to hold less than about 14-20 cc's of polarized ¹²⁹Xe gastherein. For venous injections, the dose container can be sized andconfigured to hold less than about 100 cc's of polarized ¹²⁹Xe gastherein. The container can be a syringe configured with a primary bodywith a wall having outer and inner surfaces, and the inner surface isformed from a material which reduces contact induced polarization decayassociated therewith. Preferably, the syringe body is operablyassociated with a capillary stem and valve to control the exit of gasfrom the syringe. The syringe body can also include an NMR excitationcoil mounted thereon. For delivery, it is preferred that a catheter ispositioned in a subject at the desired injection site (corresponding tothe desired target image region in the subject). The catheter caninclude or be operably associated with a frit or needle which is formedor coated with a polarization friendly material (such as a gold platedor aluminum needle). The frit or needle may also be configured and sizedto reduce the bubble size to at or below about a 10 micron diameter atinjection. This reduced bubble size may be particularly suitable forarterial injection sites.

[0037] In certain embodiments, an injection system for administeringpolarized gas to a subject can include (a) a polarized noble gas supply;(b) a catheter configured and sized for intravenous or intrarterialplacement in a subject in fluid communication with the supply ofpolarized noble gas; and (c) an injection head positioned in a distalportion of the catheter. The injection head can comprise multipleorifices which are configured so that, in operation, hyperpolarized gasflows therethrough and out of the catheter into the subject. Theorifices can be sized with a width which is between about 1 nm-50 μm,and typically between about 0.01-10 μm.

[0038] In certain embodiments, the system can include an additive source(such as an emulsifier source) and a mixing chamber positionedintermediate the orifices and the additive or emulsifier and polarizedgas sources to mix the hyperpolarized gas and the additive or emulsifierprior to expulsion from the injector head orifices (typically it ismixed in situ as the gas flows away from the gas source toward the exitorifice(s) in the injection head). The system may also include a heatingor cooling means to promote the generation of a fine dispersion of gasmixture from the injection head (which typically resides in an IVinserted into the body).

[0039] In preparing the syringe, catheter, injection system, and/orconduit associated therewith for use according to the present invention,CO₂ can be employed as a purge gas to prepare the container and reducethe likelihood of introducing nitrogen via injection into a subject(potentially leaving residual or traces of CO₂ rather than nitrogenwhich has been conventionally used to prepare the polarized gascontainers). As such, the injectable ¹²⁹Xe may include small quantitiesor traces of CO₂ therewith.

[0040] The system may include a resilient dose bag having external wallswhich are responsive to the application of pressure thereagainst and aquantity of hyperpolarized gas held in the dose bag along with aninflatable bladder which is sized and configured to receive at least aportion of the dose bag therein. In operation, the inflatable bladder isinflated to press against the dose bag external walls to thereby expel aquantity of the hyperpolarized gas from the dose bag.

[0041] In one embodiment, the present invention is configured to employa dual path hyperpolarized gas product delivery system. For a manualpresentation and delivery, a technician can deliver the ¹²⁹Xe (inject)and then trigger a switch in the MRI unit indicating that the deliveryis complete. The MRI unit, in response to activation of the switch, caninitiate the imaging procedure such that it commences within therequired polarization life at the target-imaging region. The MRI unitcan also have a timer operably associated therewith which can alert thetechnician when it is acceptable to deliver the inhalation dose. Theinhalation dose can be an optional delivery which is withheld if noreasonable indicia of perfusion deficits are indicated by NMR signalobtained based on the injected dose. Of course, the injection dose andthe inhalation dose order can be reversed, wherein the injection dose isadministered second. In addition, automated delivery and sequencingmethods can also be employed as will be appreciated by one of skill inthe art.

[0042] For concurrent delivery, the system can include a user audibleand/or visual alert which is responsive to one or more of the dispensingsystems (it is activated when a gas or liquid polarized productcommences delivery at an IV or inhalation or other administration) thatallows the dispensing of more than one dose/path of gas (such as theinhaled and injected gas) to be timed or substantially concurrently (orat a predetermined or desired interval) administered. This canfacilitate the effective delivery and initiation of imaging sequenceswhich can be important due to the limited polarization life of thepolarized gas product in the blood.

[0043] An additional aspect of the present invention is a method ofevaluating the efficacy of targeted drug therapy, comprising the stepsof delivering a quantity of a predetermined gene treatment preparationor pharmaceutical drug in vivo into a mammalian subject having a targetsite and a treatment condition; injecting a predetermined quantity ofgaseous phase hyperpolarized ¹²⁹Xe in vivo into a mammalian subject suchthat the hyperpolarized gas is delivered to the target site in gaseousor dissolved form; generating a NMR image or spectroscopic signal of thetarget site associated with the injected hyperpolarized ¹²⁹Xe gas; andevaluating the NMR image or spectroscopic signal to evaluate theefficacy of the gene treatment or drug on the treatment conditionadministered in the delivering step.

[0044] In one embodiment, the method further comprises the step ofacquiring at least two sets of data, the data representing twotemporally spaced apart points in time, to evaluate if the treatmentcondition is influenced by the drug or gene therapy introduced in thedelivering step. Of course, the evaluation may be performed withoutregard to toxicity and/or survival if done in connection with animalresearch.

[0045] Another aspect of the invention is a method of determining thepresence of cancerous tissue, comprising the steps of delivering aquantity of a pharmaceutical drug in vivo into a mammalian subjecthaving a target site associated with a suspect mass or tissueabnormality; injecting a quantity of gaseous hyperpolarized ¹²⁹Xe invivo into a mammalian subject such that the hyperpolarized gas isdelivered to the target site; generating a NMR image or spectroscopicsignal of the target site corresponding to the injected hyperpolarized¹²⁹Xe gas; and evaluating the NMR image or signal for the presence orabsence of signature patterns in the generated image or signalassociated with the presence or absence of cancer.

[0046] An additional aspect of the present invention is an injectable¹²⁹Xe gas product, the ¹²⁹Xe gas product formulated as a sterilenon-toxic hyperpolarized gas formulation which consists essentially ofisotopically enriched ¹²⁹Xe in gaseous phase which is injected in vivoin a quantity of less than about 20-100 cubic centimeters.

[0047] Similarly, another aspect of the present invention is aninjectable ¹²⁹Xe gas pharmaceutical grade product, the productformulated as a sterile non-toxic product which consists essentially of¹²⁹Xe in gaseous phase and traces of CO₂, wherein the injectable gasproduct is configured to be dispensed in vivo.

[0048] The present invention is advantageous because relatively smallquantities of (preferably isotopically enriched) hyperpolarized ¹²⁹Xegas with relatively predictable or known polarization levels can providehigh-quality MRI images or spectroscopy data with clinically usefulsignal resolution for in vivo tissue and/or vasculature. Indeed, in onepreferred embodiment, the pulmonary embolism detection method can beperformed as a relatively quick screening method typically with highquality diagnostic information about the circulatory path, such as inunder about 15 minutes. In this embodiment, it is preferred that both aninhalation (ventilation) and injection delivery of hyperpolarized gasare used to generate a combined (dual) introduction path. That is,inhalation can provide a first order image or ventilation image of thelungs. However, the gas migrates into the vasculature and/or is uptakenby the blood stream and, thus, is introduced into a pulmonary vein(s).This uptake can provide MRI or NMR venous spectra/information of thevenous side of the circulatory system. In contrast, the injection into avenous pathway can yield NMR arterial signal information (generallydescribed, the ¹²⁹Xe gas injected in a vein travels/flows to the rightside of the heart and then into a pulmonary artery). Therefore, the dualintroduction path can provide a more complete image/signal of both thearterial and venous side of the pulmonary vasculature. Conveniently, byusing polarized ¹²⁹Xe gas both as the inhalation and injection NMRmedium, the pulmonary embolism screening method can use the same NMRchest coil for the excitation and detection of the ¹²⁹Xe signalsassociated with the inhaled/perfusion dose and the injected dose.

[0049] Of course, direct injection of ¹²⁹Xe polarized gas to aparticular target site such as a tumor can allow for additionaldiagnostic information over many conventional procedures. For example,in vivo cancerous tumors can be characterized by the presence ofincreased random blood vessel growth (a condition known asangiogenisis). This is in contrast to benign cysts. Taking advantage ofthis characteristic and the NMR signal information available usingdirect ¹²⁹Xe polarized gas injection, the present invention can analyzein vivo a target in an organ such as a tumor in a breast. For example, aneedle can be inserted or injected to the suspect region in the breastvia conventional MR guided needle placement and ¹²⁹Xe can be releasedthereat (along with or in lieu of removing biopsy materials). Signaturepeaks in spectroscopy signals (or improved image resolution attributedto the hyperpolarized ¹²⁹Xe signal) can indicate the presence of cancervia the increased peak in the signal due to the increased blood (and theinjected xenon's solubility therewith). Of course, other contrastmechanisms like chemical shift, T₂*, diffusion, T₁, and the like, canalso be employed to exploit the ¹²⁹Xe NMR image or spectroscopic signalin the tumor.

[0050] In addition, the present invention preferably employs a reliablequantitative concentration and/or predictable injection quantity. Thispredictable concentration of polarized gas can provide more predictableand reliable signal intensity for the associated MRI image, which, inturn, makes the method clinically useful as well as easier to correlate,patient to patient, or in a single patient over time. Preferably, theinjectable quantity is selected to correspond to the introduction(injection) site; the venous side can use increased quantities comparedto the arterial side (the venous side injections preferably sized atabout 100 cc's or less while the arterial injections are typically sizedat about 14-20 cc's or less.

[0051] In addition, the gas is preferably injected in a manner whichfacilitates reduced size bubbles introduced or formed by the injectingof gas. Controlling one or more of bubble size based on its responsiveparameters, the quantity of gas administered, and/or injection rate(release) (as well as the configuration of the nozzle or exit chamber)of the gas can assure that the gaseous delivery to vasculature is donein an effective manner.

[0052] In one embodiment, the in vivo introduction of a suitablesurfactant temporally and spatially proximate to (preferably upstream)the actual injection of the gas (temporally before or concurrent to thegas injection) can facilitate the dissipation or decreased size ofinjected bubbles in the venous and/or arterial system (depending on theinjection site).

[0053] Further, the present invention recognizes that in order to allowthe injected xenon gas sufficient time to enter the pulmonaryvasculature, the NMR scanning is preferably delayed a sufficient amountof time after injection to allow for same, typically about 5-10 secondspost-injection. On the upper time limit, the NMR scan is also preferablyperformed within about one minute post-injection (and preferably 30seconds after injection) as the polarization level will decay to anundesirable level relatively shortly after introduction into the body.Of course, multiple serially successive quantities of administeredinjection doses can be administered during the imaging session forobtaining a plurality of sequential or multi-shot images.

[0054] The dispensing methods, containers, and other apparatus of thepresent invention are advantageously configured to facilitate a longerT₁ for the polarized gas and, thus, to promote a single-bolus sizedformulation with a predictable level of polarization in a hyperpolarizedproduct. Further, the ¹²⁹Xe injectable gas product can be delivered andformulated in a way which allows the gas to be analyzed to determine itspolarization level prior to delivery to thereby confirm the efficacy ofthe product just prior to (or in a preferred temporally appropriatepoint prior to) introduction into the patient.

[0055] Further, the present invention provides methods for sizing thelength of a capillary stem on a container having a primaryhyperpolarized gas holding chamber with a volume, the capillary stemhaving a volume which is substantially less than that of the gas holdingchamber and includes a wall defining a flow channel aperture having aradius or width and a length. The wall has a gas-contacting surfaceformed of a material having a relaxivity value for a selectedhyperpolarized gas associated therewith. The method comprises the stepsof defining a capillary stem aperture size; establishing a relaxivityvalue for the material forming the capillary wall; and calculating anoptimal capillary stem length. Similarly, the present invention canconfigure containers with capillary lengths chosen to increase thepolarized life of the gas held therein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0056]FIG. 1A is a schematic illustration of the human circulatorysystem illustrating the venous and arterial portions thereof Thedeoxygenated blood is represented by the lighter/white regions and theoxygenated blood is represented by the darkened regions.

[0057]FIG. 1B is a schematic illustration of preferred anatomicinjection sites associated with MRI angiographic imaging regionsaccording to the present invention. Region “A” represents the cranium,region “B” represents the lower extremities, region “C” represents thepulmonary vasculature, region “D” represents the renal portion of thecirculation system or vasculature, and region “E” represents the hepaticportion of the vasculature. Exemplary injection sites or delivery pathsassociated with the imaging regions are noted by the numeric subscript.For example, for pulmonary vasculature imaging region represented by theletter “C”, a first injection site C₁ and a second ventilation deliverypath C₂ are shown according to the present invention. In contrast, theremainder of the regions are shown with one or more injection sites.

[0058]FIG. 2 is a schematic illustration of a MRI system for pulmonaryembolism screening according to a preferred embodiment of the presentinvention. As shown, the subject is receiving two separate doses ofhyperpolarized gas, one of which is injected ¹²⁹Xe gas and one of whichis inhaled gas (ventilated).

[0059]FIGS. 3A is a cross-sectional view of a vein.

[0060]FIG. 3B is a cross-sectional view of an artery.

[0061]FIG. 4 is a side view of different sized blood vesselsillustrating different flow rates corresponding to diameter of thevessel at a particular pressure.

[0062]FIG. 5 is a schematic illustration of a controlled gas deliverysystem according to the present invention.

[0063]FIG. 6 is a side view of an alternate controlled gas deliverysystem according to the present invention.

[0064]FIG. 7A is a section view of the syringe taken along the linedrawn as 7A-7A in FIG. 6.

[0065]FIG. 7B is a side view of a hyperpolarized gas injection devicewith a NMR excitation coil mounted thereon according to the presentinvention.

[0066]FIGS. 8A and 8B are perspective views of yet another alternativegas delivery system according to the present invention. FIG. 8Aillustrates the gas container with an inflatable inner membrane member.FIG. 8B illustrates the inner membrane member expanded to expel or forcea quantity of hyperpolarized gas out of the chamber. FIG. 8B alsoillustrates a NMR monitor coil positioned to detect the polarizationlevel of the gas, preferably just prior to dispensing into the subject.

[0067]FIG. 8C is an enlarged end view of the exit surface of an injectorhead according to embodiments of the present invention.

[0068]FIG. 8D is a schematic drawing of an injection system according toembodiments of the present invention.

[0069]FIG. 8E is a schematic drawing of an alternative injection systemaccording to embodiments of the present invention.

[0070]FIG. 8F is an enlarged sectional view illustrating at least twoseparate flow channels and a mixing chamber upstream of gas outlet portsaccording to embodiments of the present invention.

[0071]FIG. 8G is a greatly enlarged partial side view of an injectionhead having a convergent nozzle configuration according to embodimentsof the present invention.

[0072]FIG. 8H is a greatly enlarged partial sectional side view of anend portion of an injection head according to embodiments of the presentinvention.

[0073]FIG. 8I is a greatly enlarged partial sectional side view of analternate configuration of an end portion of an injection head accordingto embodiments of the present invention.

[0074]FIG. 9 is a graph of a timing sequence of a quantity of injectedgas and a MRI pulse imaging sequence according to a preferred embodimentof the present invention.

[0075] FIGS. 10A-10P are graphs of NMR spectra obtained about every 0.5seconds via a whole body imager based on about a 3 cc polarized ¹²⁹Xegas injection into the vein of a rabbit (total of elapsed time from FIG.10A to 10P being about 8 seconds). The graphs illustrate that the gasremained substantially in the gas phase (substantially insoluble as ittraveled through the bloodstream during the image acquisition). Thesignal strength at 8 seconds (FIG. 10P) being about 0.65 that of theoriginal signal (FIG. 10A).

[0076]FIG. 11 is a graph which illustrates a relationship which canassess an increased, and preferably, optimum capillary length forcontainers housing ¹²⁹Xe. The graph shows a maximum or optimal T₁obtained at particular length and that for larger or smaller lengths,the T₁ is reduced over the T₁ obtainable at the optimal length. The samerelationship can be used to determine capillary lengths for ³He andthese lengths will be substantially longer for similar T₁'s andsimilarly sized containers and stem radiuses.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION

[0077] The present invention now will be described more fullyhereinafter with reference to the accompanying drawings, in whichpreferred embodiments of the invention are shown. This invention may,however, be embodied in many different forms and should not be construedas limited to the embodiments set forth herein; rather, theseembodiments are provided so that this disclosure will be thorough andcomplete, and will fully convey the scope of the invention to thoseskilled in the art. Like numbers refer to like elements throughout. Inthe figures, certain layers, regions, or components may be exaggeratedor enlarged for clarity.

[0078] As known to those of skill in the art, polarized gases arecollected, frozen, thawed, and used in MRI applications. For ease ofdescription, the term “frozen polarized gas” means that the polarizedgas has been frozen into a solid state. The term “liquid polarized gas”means that the polarized gas has been or is being liquefied into aliquid state. The term “gaseous” hyperpolarized ¹²⁹Xe indicates thegaseous phase of the “hyperpolarized ¹²⁹Xe gas”. Thus, although eachterm includes the word “gas”, this word is used to name anddescriptively track the gas which is produced via a hyperpolarizer toobtain a polarized “gas” product. Thus, as used herein, the term “gas”has been used in certain places to descriptively indicate ahyperpolarized noble gas product and may be used with modifiers such assolid, frozen, and liquid to describe the state or phase of thatproduct.

[0079] Various techniques have been employed to accumulate and capturepolarized gases. For example, U.S. Pat. No. 5,642,625 to Cates et al.,describes a high volume hyperpolarizer for spin polarized noble gas andU.S. Pat. No. 5,809,801 to Cates et al. describes a cryogenicaccumulator for spin-polarized ¹²⁹Xe. U.S. Pat. No. 6,079,213 toDriehuys et al., entitled “Methods of Collecting, Thawing, and Extendingthe Useful Life of Polarized Gases and Associated Apparatus,” describesan improved accumulator, collection and thaw methods, and xenon gasheating means. The disclosures of these documents are herebyincorporated by reference as if recited in full herein.

[0080] As used herein, the terms “hyperpolarize”, “polarize”, and thelike, mean to artificially enhance the polarization of certain noble gasnuclei over the natural or equilibrium levels. Such an increase isdesirable because it allows stronger imaging signals corresponding tobetter MRI (and spectroscopy) images of the substance and a targetedarea of the body. As is known by those of skill in the art,hyperpolarization can be induced by spin-exchange with an opticallypumped alkali-metal vapor or alternatively by metastability exchange.See Albert et al., U.S. Pat. No. 5,545,396. Other methods may also beused, such as dynamic nuclear polarization (“DNP”) and “brute force”methods which propose to cool the ³He or ¹²⁹Xe to very low temperaturesand then expose them to very high magnetic fields to enhance the thermalequilibrium polarization.

[0081] Generally stated, the present invention recognizes that directgaseous injection of hyperpolarized ¹²⁹Xe can be a viable, safe, andeffective delivery method when the gas is formulated and delivered in amanner which reduces the potential for formation of emboli within thevasculature. Unlike many previous injectable formulations, the presentinvention employs a gaseous formulation of inert polarized (preferably“isotopically enriched” polarized ¹²⁹Xe gas as will be discussed furtherbelow) ¹²⁹Xe which is packaged in a polarization friendly (increasedlonger relaxation life) container or syringe to provide an injectablepharmaceutical grade gas phase product. The gas phase injectableformulated hyperpolarized ¹²⁹Xe can be an effective image enhancingproduct when delivered at a controlled rate and/or quantity with apredictable polarization level which can provide improved imageresolution and/or diagnostic capability without the need for additionalliquid carrier agents and mixing. Direct gaseous injection has manyadvantages that can not only simplify the diagnostic procedure, it canalso restore the sensitivity of ¹²⁹Xe to its environment and can improvethe delivery efficiency of polarized ¹²⁹Xe to target tissues. Thegaseous injection can be performed such that it remains substantiallynon-dissolved in the bloodstream over about 8-10 seconds from the timeof injection, or can be performed such that it is at least partially,and even substantially, dissolved proximate to the injection site orwithin a short period from the time of injection (i.e., less than about2-4 seconds).

[0082] Further, in certain embodiments the gaseous formulation caneliminate the use of an external fluid-mixing step. Still further, thehyperpolarized ¹²⁹Xe can be contained in a specialized gas syringe withincreased relaxation times as will be discussed further below. Incertain embodiments, the degree of polarization is measured via an NMRcoil located on the dispensing container itself which can be utilizedjust prior to administration. Thus, the NMR signal strength can be moreaccurately/reliably correlated to the polarization level and also theadministration can be performed in a relatively calm, relaxed manner,without the impending threat and constraints of rapid decay elicit inmany conventional short T₁ formulations.

[0083] Referring now to FIG. 1A, a human circulatory system 10 isschematically illustrated. The oxygenated blood within the vasculatureis represented by the darker regions while the deoxygenated blood isrepresented by the white or lighter regions.

[0084] As used herein the term “vasculature” includes boundary tissue,cells, membranes, and blood vessels such as capillaries, venules, veins,arteries, arterioles, and the like associated with the circulatorysystem and blood flow path and/or channels of blood. Typically, as shownin cross sectional views in FIGS. 3A and 3B, the artery flow channels 30a are smaller and more rigid and round compared to the vein flowchannels 30 v.

[0085] The gaseous ¹²⁹Xe injection of the present invention has somesimilarities to a technique presently used, called digital subtraction(DSA) CO₂ angiography. Generally described, in this conventionalprocedure, CO₂ is rapidly injected to displace a portion of the blood.An X-ray image is taken quickly after injection. Where the CO₂ hasdisplaced the blood, there is reduced X-ray opacity and the imageappears brighter. Typically, a second X-ray is taken without CO₂injection and the two images are digitally subtracted to show thecontrast. CO₂ DSA is used instead of traditional iodinated contrastagents because of the “nephrotoxicity” of iodine-based contrast agents.The volumes of CO₂ injected range from roughly 10 cc's to 50 cc's (thelarger quantity for larger blood vessels). In addition, the injectionrate is quite rapid (10 ml/s to 10 ml/sec) inasmuch as contrast onlyresults from the displacement of blood. Generally stated, afterinjection, CO₂ is efficiently dissolved into the blood and exhaled uponpassage through the pulmonary capillary bed. Stated differently, CO₂exits the blood into the lung alveoli via diffusion through pulmonarycapillary. A review of this technique has been presented by Hawkins andco-workers. Kerns et al., Carbon Dioxide Digital SubtractionAngiography: Expanding Applications and Technical Evolution, 164 Am.Jnl. Radiology, pp. 735-741 (1995).

[0086] The feasibility of gaseous ¹²⁹Xe injection, particularly forarterial injections, may appear problematic. For example, it is knownthat arterial injections of air can lead to an undesirable air embolus.Although with intravenous (IV) injection the introduction of air is lessof a concern, great care is typically taken to avoid such occurrences.The injection of CO₂ is successful because of its high solubility inblood and the body's unique ability to remove it. The solubility of CO₂in blood and plasma can be difficult to measure because it is chemicallymetabolized. However, its solubility in water is 0.63 and it has beenmeasured in RBC (red blood cell) ghosts to be about 1.0. Table 1 belowshows the solubilities of other relevant gases in water plasma andblood. TABLE 1 Solubilities of Gases Gas Water Plasma Blood Other He0.0098 0.0086 0.0094 0.0105 (lung) N₂ 0.0143 0.0134 0.0148 0.109 (RBCghosts) O₂ 0.0271 0.0243 0.0261 0.13 (RBC ghosts) CO₂ 0.631  — — 1.0(RBC ghosts) Xe 0.089  0.105 0.167  0.181 (liver)

[0087] As CO₂ in plasma and blood are metabolized before themeasurements can be obtained, no numbers are listed for these entries inTable 1. Nonetheless, it is believed that the solubility that is ofprimary interest for the discussion herein and that the CO₂ metabolismcan be disregarded for the purposes of this comparison.

[0088] Table 2 below shows the solubilities of these gases relative toCO₂ (i.e., the relative solubility “S_(r)” is represented by the ratioof:

(Solubility of named gas in water)/( Solubility of CO₂in water). TABLE 2Relative Solubility (S_(r)) Gas Sr (relative) CO₂ 1    Xe 0.14  O₂ 0.043N₂ 0.023 He 0.016

[0089] Table 2 illustrates the higher solubility of xenon compared tothe major constituents of air (O₂ and N₂) but also shows that CO₂ isconsiderably more soluble than xenon. Therefore, the present inventionrecognizes that direct gaseous injection of polarized ¹²⁹Xe can be auseful in vivo diagnostic NMR imaging tool and also recognizes thatproper sizing of the injectable quantities and/or the injection ratesare important considerations for achieving same. Accordingly, thepresent invention provides a maximum preferred arterial xenon injectionvolume by comparing the solubilities of xenon and CO₂. Maximum CO₂injection volumes are typically limited to about 50-100 cc's of gas. Bytaking the relative solubilities above into consideration, the maximumxenon injections can be predicted to be about 0.14 times the quantity orvolumes of CO₂. Thus, particularly for arterial injection sites, for aCO₂ volume of 100 cc's, the xenon injection volume is preferably limitedto about 14 -20 cc's. For the smaller range of injected CO₂, such as a10 cc injection volume, a 1.4 -2.0 cc volume of polarized ¹²⁹Xe gas ispreferably dispensed according to the present invention.

[0090] In contrast, for non-arterial sites, such as for venous injectionsites, a larger injection quantity may be tolerated. That is, it isknown that the introduction of air into venous sites which is on theorder of 300-400 cc's can be particularly troublesome and evenpotentially fatal. Xenon, although less soluble in blood than CO₂, isabout 10 times more soluble than air (i.e., it can dissolve faster inblood than air). Thus, even with a safety factor, the venous siteinjections can be typically sized at quantities in the range of about100 cc's, although preferably sized at less than 100 cc's. Of course,such injection volumes also depend on the vessel type and size beinginjected into.

[0091] Along with the quantity of the gas formulated for injection, thegenerated bubble size and/or bubble dissipation can be importantconsiderations for in vivo applications, particularly for arterialinjection sites. In certain embodiments, a surfactant can be injectedproximate in time and location to the gas injection site to either helpdissipate the size of the bubble and/or to lower the blood surfacetension. Surfactants have been studied by van Blankenstein et al. to aidin the recovery from venous air embolism. See J. H. van Blankenstein etal., Cardiac Depression after Experimental Air Embolism in Pigs: Role ofAddition of a Surface-Active Agent, 34 Cardiovascular Research, pp.473-482 (1997). In this study, air bubbles with a diameter of about 150μm were injected into the left anterior descending coronary artery inthe presence or absence of antifoam. A 1:250 dilution of siliconeantifoam 1510 EU (from Dow Coming) in pure water was used. The studyindicates that the in vivo introduction of surfactants can reduce bubbledissipation time in blood.

[0092] It is contemplated by certain embodiments of the presentinvention that any suitable in vivo physiological compatible oracceptable surfactant can be employed whether of natural (human orbovine) or synthetic origin, and/or combinations thereof. Suitablephysiologically acceptable formulations are known to those of skill inthe art. See e.g., U.S. Pat. No. 4,826,821 to Clements, U.S. Pat. No.4,312,860 to Clements, and U.S. Pat. No. 5,309,903 to Long (alldiscussing the use of surfactants in vivo for respiratory distresssyndrome). These disclosures are hereby incorporated by reference as ifrecited in full herein. See also Horbar et al., A MulticenterRandomized, Placebo-controlled Trial of Surfactant Therapy forRespiratory Distress Syndrome, 320 The New England Jnl. of Med., No. 15,pp. 959-965 (Apr. 13, 1989) (discussing organic solvent extract ofcow-lung fortified with dipalmitoylphos-phatidlydhloine known as“SURVANTA” from Abbott Laboratories in Chicago, Ill.). Preferably, thesurfactant is also chosen such that it is substantially non-depolarizingto the hyperpolarized state of the gas. The surfactant may be deliveredvia injection or insertion into the body proximate to the target gasinjection site such that it facilitates bubble dissipation or reducesblood surface tension while also being substantially non-depolarizing tothe polarized state of the gas (to help reduce the formation of emboliattributed to the injected gas).

[0093] As briefly discussed above, the injection of the gas can becarried out in a manner which reduces or limits the bubble sizeassociated therewith. To better understand bubble dissipation, one canmodel a string of contiguous bubbles as a cylinder to look at thediffusion of the gas out of the “cylinder” into the surrounding fluid toanalyze how the bubble volume or radius decreases with time. Presser etal., in modeling a simulation as stated above, noted that the bubbleradius “r” versus time can be represented by the equation:

dr/dt=−KΔP/[rIn (R/r)]

[0094] where “K” is Krogh's coefficient (the product of solubility “S”and diffusion coefficient “D” of the gas in the surrounding fluid), “ΔP”is the pressure difference between gas in the bubbles and gas in thealveoli and “R” is the distance from the center of the bubbles to theinner edge of the adjacent alveoli. See Presser et al., Fate of AirEmboli in the Pulmonary Circulation, 67 J. Appl. Physiol. 5, pp.1898-1902 (1989). To solve the equation requires numerical techniques,but the relationship can be generally characterized as beingsubstantially linear for air down to about a 10 μm radius bubble, atwhich size the rate of dissipation is increased (i.e., it becomessteeper and more exponential-like). Presser et al. also notes that forair bubbles with radius' greater than about 10 μm, dr/dt=−0.132 μm/s.Thus, generally speaking, a 30μm radius air bubble takes about 230seconds to dissipate.

[0095] In contrast, as recognized by the instant invention, xenon bubbledissipation occurs at a faster rate than air. That is, for comparativeanalysis, it is believed that one can evaluate the Krogh's coefficient(S×D) for Xe relative to air. The diffusion coefficient is substantiallythe same and can be cancelled out. For example, Xe in H₂O is about1.9×10⁻⁵ cm^(2/)s while methane and water itself are at 2 and 2.3×10⁻⁵cm²/s, respectively. Thus, solubility “S” becomes the important factor.Therefore, approximating air as nitrogen, the solubility ratio of xenongas to nitrogen gas in blood is (0.167/0.0148), or about eleven (11).Accordingly, the bubble dissipation rate (dr/dt) for xenon is estimatedat −1.5 μm/s. The same 30 μm radius bubble will dissipate in about 20seconds. This additionally supports the direct injectability of ¹²⁹Xepolarized gas into systemic arterial and venous circulatory injectionsites.

[0096] Air bubbles of various sizes have been produced for injectioninto a coronary artery. See Van Blankenstein et al., Heart Functionafter Injection of Small Air Bubbles in Coronary Artery of Pigs, 67 J.App. Physiol. 5, pp. 1898-1902 (1989). In this study, air bubbles of 75,150, and 300 μm diameter were formed with tolerances of about 10 μm.Generally stated, a micropipette with a constant-pressure source of airwas used to form the desired bubble size. Factors impacting theformation of bubble size were pipette diameter, air (gas) pressure, andthe flow of fluid through the pipette (flow volume in the artery mayalso be parameter to be considered). It is anticipated that calibrationcurves can be generated based on these factors (i.e., bubble-sizedependent variables) to generate the desired bubble size.

[0097] In any event, in certain embodiments, the hyperpolarized ¹²⁸Xegas can be directly injected into the subject, such as into the bloodstream of the subject, in bubble-sizes in the range of between 1 nm to300 μm, and preferably in the range of between about 0.5-10 μm.

[0098] In order to generate a series of sequential bubbles forinjection, it is preferred that a frit or custom fabricated lumen (smalldiameter) configuration can be employed and/or with a controlledpressure set to form the desired bubble size (not shown). In certainembodiments, the frit may comprise glass (such as a substantiallymagnetically pure aluminosilicate or surface coated glass to reducesurface relaxation effects). A differently sized/configured frit (exitdiameter/shape) or lumen may be formed for various injection sites(particularly to facilitate the production of smaller bubble size forarterial applications) and located such that it is in fluidcommunication with the conduit or even integrated into the syringe or IVor other catheter body itself.

[0099] In any event, a polarized ¹²⁹Xe gas injection quantity of as lowas under 5 cc's, such as just 1-2 or 1-3 cc's, but typically at leastabout 14-20 cc's (depending upon the injection site), can provideimproved signal strengths even over larger amounts with conventionalhyperpolarized inhalation techniques (although greater quantities can beused as discussed above). For example, the brain-imaging exampledescribed above shows that an injection of just 1, 2, or 3 cc's of ¹²⁹Xecan result in larger signals than can be typically achieved throughinhalation of 1 liter of hyperpolarized ¹²⁹Xe. The signal strength canbe improved to be even stronger if isotopically enriched polarized ¹²⁹Xeis employed.

[0100] Furthermore, unlike injection of CO₂, the ¹²⁹Xe injection doesnot have to be performed at a rate which is fast enough to displace theblood. The ¹²⁹Xe can be readily imaged if it is (a) dissolved in theblood, or (b) if it remains (largely or in smaller amounts) in the gasphase as it travels in the bloodstream for imaging purposes.

[0101] In the case of an arterial injection where rapid dissolution ofthe xenon into the blood stream may be desired, the gas injection can beperformed at a rate which is sufficiently slow so that the xenon cansubstantially dissolve into the blood stream as it is injected therein.Mathematically stated, this injection rate limit may be set at about${\frac{}{t}V_{Xe}} = {\lambda \quad Q}$

[0102] where “λ” is the xenon solubility in blood and “Q” is thevolumetric blood flow rate in the vessel being injected. Injection atthis speed can result in substantially fully xenon-saturated blood inthe injection region. In certain embodiments, the injection rate can beselected such that it is less than the blood flow rate within theinjection site. The injection rate can be carried out such that it isless than about 25-50% of the blood flow rate, particularly for arterialinjection sites. For example, blood flow in the hepatic artery in anaverage adult is roughly 5.8 cc/s, so it is anticipated that a xenon gasinjection rate of about 1-5 cubic centimeter per second (cc/s), and incertain applications 2.9 cc/s or less, or in other applications about 1cc/s or less should be physically tolerable and sufficiently rapid todeliver a quantity which can yield clinically acceptable NMR imagesand/or signals.

[0103]FIG. 4 illustrates three different flow rates and associatedvessel diameters (at flow rates smaller than the hepatic arterydescribed above (5.8 cc/s=348 ml/min)). Of course, especially for moredistal target imaging regions and/or smaller injection quantities, orwhere is desirable to retain a larger portion of the gas non-dissolvedin the bloodstream, faster injection rates can be employed.

[0104] Venous injections using even larger xenon volumes or quantitiesand/or more rapid ¹²⁹Xe injection rates (as well as larger bubble size)as compared to the arterial injection sites may also be suitable. Forexample, for 100 cc's of injectable gas, a suitable injection rate canbe about 2-3 cubic centimeters per second. In other applications, ratessubstantially equal to or less than about 2 cc/s may be appropriate. Theinjection rates can be controlled in a number of ways such as via manualor automated (or semi-automated) operation as will be appreciated bythose of skill in the art. See e.g., U.S. Pat. No. 3,623,474 to Heilmanet al. and U.S. Pat. No. 5,322,511 to Armbrusther et al. (describingpower injection equipment). The contents of these documents are herebyincorporated by reference as if recited in full herein.

[0105] In contrast to inhalation methods, the gas-injection methodallows smaller amounts of hyperpolarized gas to be effectivelyadministered in smaller clinically effective doses. This smaller dosegas-based administration also allows for a commercially advantageous useof isotopically enriched (typically more a expensive formulation)polarized ¹²⁹Xe. “Isotopically enriched” means ¹²⁹Xe which has beenenriched over natural levels (the natural level is about 26%).Preferably, the ¹²⁹Xe gas which is polarized is enriched to a levelwhich is isotopically enriched to at least about 50%, and morepreferably enriched to at least about 70%, and still more preferablyenriched to at least about 80%.

[0106] The present invention now allows the arterial side of thepulmonary vessels to be directly imaged rather than inferring orpredicting ventilation defects vicariously as proposed in conventionalinhalation based systems. That is, as discussed above, injection into avein, allows the polarized gas to travel in the bloodstream through theheart and then into the pulmonary artery. In contrast, inhalation allowsventilation-based images and then as the polarized gas travels into thebloodstream through the pulmonary vasculature, it travels into thepulmonary venous circulatory flow path and can allow signal informationcorresponding to the venous system.

[0107] Still further, the imaging techniques which employ directinjection of hyperpolarized gas can provide perfusion images which areunobscured by ventilation defects typically associated with conventionalinhalation-based images. That is, the inhalation methods may show aperfusion defect where a ventilation defect resides, because gas may beblocked from entering the vessels. In contrast, direct gas injectionmethods of the present invention can show “real” perfusion defects,i.e., defects attributed (solely) to perfusion blockage. In addition, asnoted above, using both inhalation and injection delivery of polarizedgas as described herein can provide complementary diagnostic informationand detail.

[0108] It should also be noted that NMR imaging or signal acquisition of¹²⁹Xe in the gas phase in the blood can provide increased an increasedT₁ over that of the gas dissolved in the blood. In addition, ¹²⁹Xedissolved into the blood may provide a broader spectrum attributed tothe rapid exchange between the ¹²⁹Xe in RBC's and plasma. Unfortunately,a broad spectral line typically translates to a relatively short T₂*.Therefore, sizing and delivering the injectable dose so that it remainssubstantially as a gas in the bloodstream can allow longer dataacquisition times and/or improved images or signals therefrom.

[0109] Of course, the injection rate or release rate (volume over time)can be selected such the polarized gas is solubilized (substantiallydissolved) into the blood proximate to the injection site. Alternately,the injection rate can be selected such that the gas is only partiallyor insubstantially solubilized in the blood proximate to the injectionsite or such that it remains in a non-dissolved state for a longerperiod of time as it travels through the bloodstream. For example,introducing the hyperpolarized gas into a vein (through the walls of thevessel) such that it retains sufficient polarization to render aclinically useful gas-phase signal after about 8-10 seconds, andpreferably after about 8-20 seconds, from the time of injection.Maintaining the hyperpolarized gas in the gas phase (such that it is notsubstantially dissolved into the bloodstream) can increase the T₁ of thegas in the body. This, in turn, can allow longer image acquisition timesduring which the signal can be picked up as a viable clinically usefuldiagnostic tool. Again, the venous injection sites can generallywithstand a greater injection volume and/or a greater delivery rate thana similarly sized arterial vessel.

[0110] Indeed, in the past, about 1 ml of air in 10 ml of saline wasinjected into the right internal jugular (IJ) vein of a human andmonitored with ultrasound for IJ valve competence. See Ratanakorn etal., Jn. Of Neuroimaging, Vol. 9, pp. 10-14 (1999). It is expected thatabout 1-10 ml of hyperpolarized ¹²⁹Xe gas, preferably configured withreduced bubble sizes (preferably at about or less than 10 microns)injected into the IJ will also yield clinically useful images and/orspectra (the hyperpolarized xenon gas bubble dissipation being about 11times faster than air in blood as discussed above).

[0111]FIG. 1B schematically illustrates suitable injection sites (shownby asterisks located on the body and a corresponding circled letter) andan associated particular tissue, organ, or vasculature target region(shown by dotted line box with and a corresponding letteridentification) according to certain embodiments of the presentinvention. Target Region of Interest Preferred Injection Site Region ACranium Neck-Carotid Artery Region B Lower Extremities Thigh-FemoralArtery Region C Pulmonary Arm, Vein (preferably in conjunction withventilated gas) Region D Renal (Kidneys) Renal Artery Region B Hepatic(Liver) Hepatic Wedge Region A Cranium Right internal juglar artery (IJ)

[0112] For example, as shown by the two circle “C” delivery sites, thepulmonary region preferably employs both an injection site to a vein inthe arm to deliver gaseous ¹²⁹Xe and an inhalation delivery of polarizedgas (the inhalation being either ¹²⁹Xe or ³He, more preferably ¹²⁹Xe).Of course, the present invention is not limited to the injection sitesand target regions disclosed above, as additional or alternate sites andadditional or alternative target regions can also be employed. Indeed,internal injection or release sites can also be employed such as throughthe use of special catheters (threaded to the desired injection ordelivery site) to deliver gas phase ¹²⁹Xe to desired target regions aswill be appreciated by one of skill in the art.

[0113] Certain embodiments of the present invention are directed to theuse of injected gaseous polarized ¹²⁹Xe for the detection of pulmonaryembolism. In these embodiments, the xenon is injected into a vein,preferably via an intravenous catheter inserted into a vein in the armand, after a suitable delay, an image of the xenon in the arterialpulmonary circulation can be made to determine if an embolus is present.For example, about 50-100 cc's of gas are injected and after about 5-25second delay period, preferably about a 5-7 second image delay period(the delay period being measured from the time after injection stops)scanning is initiated. Preferably, the scanning, based on thisinjection, is completed in less than about 60 seconds, and preferably,in about 10-45, and more preferably in about 10-20 seconds.

[0114] Alternatively, a longer delay can be applied between the time ofinjection and the image data or signal acquisition or collection so thata scan can be made of the gaseous ¹²⁹Xe as it enters in the lungresulting from the venous injection, as the gaseous ¹²⁹Xe injected in avein in the arm will subsequently dissolve only to appear or enter intothe lung if circulation is not blocked in the pulmonary arteries. Inaddition, even if the blockage is not severe enough to prevent the ¹²⁹Xewhich is injected in gas phase from entering the lung, the signalintensity of this transitory ¹²⁹Xe in the lung can vary depending on thedegree of restriction (brighter signal for smaller restrictions or freepassage, and reduced signal intensity in the lung void space for blockedor substantially restricted blood circulation passages).

[0115] In certain embodiments, such as for the lung void space image, asis well known to those of skill in the art, suitable contrast mechanismssuch as chemical shift, T₂*, diffusion, etc., can be used to distinguishbetween imaging segments which include the gaseous ¹²⁸Xe in the lung andversus (and preferably excludes or extracts) the signal data associatedwith the ¹²⁹Xe still dissolved in blood.

[0116] In certain embodiments, the pulmonary circulation image scanbased on the gas injection is coupled with a ¹²⁹Xe or ³He pulmonaryventilation scan. Using a ¹²⁹Xe ventilation scan may be preferable,because it allows the same MRI transmit/receive coil to be used for theentire procedure. The ventilation scan can be employed regardless of thedissolution or lung based image rendering methods employed on thegaseous injected polarized ¹²⁹Xe. The coupled scan can identify a V/Q(volume versus flow rate in the circulatory system) mismatch and providea potential diagnostic tool for the clinician. Alternatively, if ³He isused for the ventilation image, it is preferred that the chest coil beconfigured as a “double tuned” coil. That is, the double tuned coil istuned to operate for both ³He and ¹²⁹Xe operation.

[0117] In addition, it is preferred that the chest coils be configuredto be “proton blocked” allowing the MR scanner body coil to be used tomake a proton image of the subject in substantially the exact sameposition as the subject during the V/Q image. Thus, the proton blockedchest coil allows the body coil to obtain supplemental proton-based dataimage (without the interference of the polarized gas based coil) whichcan be combined in a signal processor with the V/Q signal data toprovide a more detailed diagnostic evaluation of the target region ofinterest. Of course, the proton-blocked configuration of the gas basedimaging coil can be operated with respect to the other gas-based imagesdescribed herein.

[0118] In certain embodiments, the inhalation based image is generatedusing polarized ¹²⁹Xe while the perfusion image is also generated usingthe injected gaseous polarized ¹²⁹Xe. An NMR system with a low fieldmagnet may be used (such as about 0.1 T-0.5 T), and the pulmonary regionimage may provide increased signal intensity from the NMR resonancesignals resulting from both the dissolved and gas phase xenon in thepulmonary region (two peaks, one associated with the RBC's and one withthe plasma). Reduction of field strength can sacrifice chemical shiftinformation between the dissolved phase and gas phase xenon in thetarget region. Nonetheless, the advantage of low-field imaging of ¹²⁹Xein blood is that the separate peaks of ¹²⁹Xe in RBCs versus plasma willoverlap and yield a larger total signal than at high-field where ¹²⁹Xein blood or plasma is separately excited and imaged.

[0119] Alternatively, a larger field magnet (>0.5 T) can be used whichseparately excites the dissolved phase and gas phase polarized gaspresent in the region of interest, and two or more data sets arecaptured via one or more excitation pulses (such as two separate imagingsequences operated at two different excitation frequencies). In thisembodiment, due to the chemical shift between the gas and dissolvedphase resonance (approximately 200 p.p.m. at 1.5 T), at least two images(both a perfusion and ventilation image) are generated on a patientduring the same imaging session (“differential” imaging). A differentialimage can provide additional diagnostic information over combined phasesignals. For example, the differential image can help distinguishbetween a pulmonary embolus and a ventilation/perfusion defectassociated with a structural anomaly as described above.

[0120] In operation, for MR images using ¹²⁹Xe as both the inhalationand perfusion medium, a first delivery of a first quantity ofhyperpolarized gas can be administered to a subject such as viainjection. After a suitable, short, delay corresponding to the desiredtarget imaging region (a delay corresponding to the time it takes thehyperpolarized gas to travel to the desired imaging site from theinjection site), a scanning sequence can be initiated. For imaging thechest region (or regions affected by the position of the chest duringbreathing activities), it is preferred that the patient hold his or herbreath to help with locational co-registration between images(especially between injection based and ventilation based images). Imagesignal data associated with the injected polarized gas according to thepresent invention is obtained before the polarization of the gas hasdecayed to an undesirable level (preferably within about 1 minute, andmore preferably within about 25 seconds from the time of injection). Oneor more additional quantities of hyperpolarized ¹²⁹Xe can besubsequently injected as needed. That is, a series of small injections(or small releases to an in situ catheter) can be made which allow acorresponding series of data collection based on the image signal dataassociated therewith.

[0121] After the injected polarized gas has cleared the target region(or the polarization has decayed to a point where it does not interferewith the ventilation image), the ventilation delivery can commence. Thatis, a second delivery of a second quantity of hyperpolarized gas isadministered. Because the second delivery is an inhalation delivery, thequantity of gas delivered is relatively large compared to the injectablequantity (about 0.75-1.5 liters versus less than about 20-100 cc'sdepending on the site). In operation, the subject inhales the secondquantity and holds his or her breath (typically for about 15 seconds).In certain embodiments, the injection based and ventilation based MRimages (or spectroscopic analysis) can be obtained during the sameimaging session, reducing co-registration issues associated withrelational positioning/re-positioning. In addition, separate (temporallyspaced apart from the injections) breath-hold delivery cycles may beused for ventilation images and perfusion directed images, which canthen be digitally combined with the injection signal data to provide amore complete image of the region.

[0122] In certain embodiments, where the pulmonary region is the targetimaging region, the combined image may be based on at least twodifferent administrations of polarized gas: (a) direct injection ofpolarized gas into a vein and (b) inhalation of polarized gas. These twodifferent administrations can result in three different deliverymechanisms of polarized ¹²⁹Xe to the pulmonary (perfusion from the ¹²⁹Xein the blood and tissues delivered from a venous injection to thearterial side of the circulatory system, perfusion into the vasculaturefrom the inhaled gas delivered to the venous side of the circulatorysystem, and a ventilation image before, during, and/or subsequent to theperfusion image with the same or additional quantities of inhaled gas).

[0123] In any event, differential imaging can provide MR images withinformation which correlates to the total region (lung space, artery andvein, and boundary regions). This technique can produce MR images whichallow diagnostic detection of emboli, perfusion defects, ventilationdefects, and other circulatory and/or respiratory system problems in thepulmonary vasculature.

[0124] In addition, for studies used to evaluate pharmaceuticaleffectiveness, the gas may be injected without regard to the toxicity orsurvival outcome. Indeed, the injection of hyperpolarized ¹²⁹Xe into aspecific target region can allow the efficacy of a pharmaceutical drug,compound, or mixture, or drug therapy aimed at a particular disease ororgan function to be evaluated and or confirmed (post mortem) that suchdrug is actually delivered to the appropriate site and/or that it has aninfluence on the targeted condition. For example, a treatment directedto cerebral disorders can be evaluated for effectiveness in suitableanimal studies by comparing the injected hyperpolarized- gas based imageof the brain over time. Similarly the effectiveness of treatment onpulmonary or cardiac functions, blood flow, or neurological conditionsand the like, may also be evaluated. In one example, targeted genetherapy directed to increasing blood vessel growth at the heart can bedelivered. Subsequently a quantity of ¹²⁹Xe gas can be injected toprovide NMR signal based on the increased xenon associated withincreased blood vessels at the target site to confirm the success of thedirected gene therapy.

[0125] In addition, it is expected that small quantities of injectedhyperpolarized ¹²⁹Xe can provide additional safe and effective in vivodiagnostic assistance in evaluating the presence or absence of cancer inmammalian subjects, particularly humans (i.e., cancerous tumor or benigncyst). For example, in vivo cancerous tumors can be characterized by thepresence of increased random blood vessel growth (a condition known asangiogenisis). This is in contrast to benign cysts. Taking advantage ofthis characteristic and the NMR signal information available usingdirect ¹²⁹Xe polarized gas injection, a target in an organ such as atumor in a breast can be analyzed in vivo. In operation, a needle can beinserted or injected to the suspect region in the breast viaconventional MR guided needle placement and ¹²⁹Xe can be releasedthereat (along with or in lieu of removing biopsy materials). Signaturepeaks in spectroscopy signals can indicate the presence of cancer viathe increased peak in the signal due to the increased blood (and xenon'ssolubility therein). In obtaining the signal or images, an appropriatefield strength should be used so as to differentiate the peaksassociated with xenon in blood versus xenon in fatty tissue as will beappreciated by one of skill in the art. Of course, other contrastmechanisms like chemical shift, T₂* and the like, can also be employedto exploit the ¹²⁹Xe image signal in the tumor.

[0126] Referring to FIG. 2, in a preferred embodiment, a patient ispositioned in a MRI system 25 and exposed to a magnetic field associatedtherewith. The MRI system 25 typically includes an NMR image processingsystem 26, a super-conducting magnet (not shown), gradient coils (withassociated power supplies) (also not shown), an excitation coil(transmit/receive RF coil) 30. Preferably, the coil 30 is configured asHelmholtz pairs oriented at 90 degrees relative to each other (notshown). Of course other configurations can also be used such asHelmholtz coil or a surface coil for imaging near surface regions of thesubject. The system also includes a RF amplifier for generating RFpulses set at predetermined frequencies (also not shown). For ¹²⁹Xeimaging at 1.5 T field strength, the MRI imaging system 25 is set tooperate in the gas-phase at about 17.6 MHz. For high field applications,the dissolved phase excitation frequency is shifted below the gas phaseexcitation frequency. For example, the dissolved phase excitationfrequency is shifted to be about 200 p.p.m. lower than the gas phaseexcitation frequency (corresponding to the chemical shift). Thus, at 1.5T, the dissolved phase ¹²⁹Xe RF excitation frequency is about 3.52 kHzlower than the associated gas-phase excitation frequency. In yet anotherpreferred embodiment, the imaging method employs a 17.6000 MHz gas phaseexcitation pulse and an associated dissolved phase excitation pulse ofpreferably 17.59648 MHz. Of course, the magnet field strength andexcitation frequency can vary as is well known to those of skill in theart.

[0127] In any event, in operation the RF pulse(s) is transmitted to thepatient to excite the nuclei of the polarized ¹²⁸Xe. The coil 30 istuned to a selected frequency range and positioned adjacent the targetedimaging region to transmit the excitation pulses and to detect responsesto the pulse sequence generated by the MRI imaging system 25. The coil30 shown in FIG. 2 is positioned to image the pulmonary vasculatureregion 12 (FIG. 1A). Preferred coils 30 for standard chest imaginginclude a wrap-around coil with conductors positioned on both the frontand back of the chest. Examples of suitable coils known to those ofskill in the art include a bird cage configuration, a Helmholtz pair orquadrature Helmholtz pairs, a surface coil, and a solenoid coil. The RFexcitation coil 30 is operably associated with the NMR image processingsystem 26 for exciting and transmitting image signal information fromthe polarized gas back to the NMR image processing system 26.

[0128] As noted above, once in position, the patient inhales a(predetermined) quantity of polarized ¹²⁸Xe gas into the pulmonaryregion (i.e., lungs and trachea). Preferably, after inhalation, thepatient holds his or her breath for a predetermined time such as 5-20seconds. This is described as a “breath-hold” delivery. Examples ofsuitable ventilation or inhalation delivered “single dose” quantities ofpolarized gases for breath-hold delivery include 0.5, 0.75, and 1.0liters of gas. Preferably, the dose at inhalation contains gas with apolarization level above 5%, and more preferably a polarization levelabove about 20%.

[0129] The MRI imaging system 25 shown in FIG. 2 includes a dual dosedelivery system 38. Thus, as shown, the dual dose delivery system 38preferably includes both an inhalation dose bag polarized gas supply 35and an injectable gas dose ¹²⁹Xe supply 40. Preferably, a non-magneticsupport 45 is employed to hold at least the inhalation dose(s) ofpolarized gas. The inhalation dose bag 35 is suspended from the support45 and a length of polarization friendly conduit 37 is in fluidcommunication with the dose bag 35 and a mask 36 positioned over theairways of the subject, so that the subject can inhale the polarizedgas, while positioned in the magnet, at the appropriate time.Preferably, the injectable dose 40 is preferably engaged with a catheteror IV 42, and is positioned proximate to the subject to reduce theconduit length 41 necessary to connect the gas to the catheter lumen 42(IV) inserted into the subject. FIG. 5 illustrates an alternateinjection site with the injected gas preferably delivered to the patientat a controlled rate, pressure, and a substantially controlled overalldispensed quantity.

[0130] One way to dispense the gas is to employ an inflatable bladderconfigured and sized to receive a major portion of the injected dose gasbag 40 (preferably configured to enclose the dose bag therein). Inoperation, at the appropriate predetermined dispensing time in theimaging cycle, a controller directs a compressor to fill the inflatablebladder to exert pressure onto the external walls of the flexiblepolymer dose bag. Air, gases or other fluids or liquids can also be usedto expand the inflatable bladder. Preferably, for preservation of thepolarization, deoxygenated water is used to reduce the migration of airinto the dose bag. Of course, air can also be used, as the inflatablebladder is preferably configured with discrete channels which are formedof a magnetic contaminant-free material such as rubber, elastomers, orother expandable materials which will act as a shield between the bagwalls and the air (i.e., the air does not directly contact the exteriorwalls of the bag 40). Preferred materials for the dose bag are describedin U.S. Pat. No. 6,128,918 and co-pending and U.S. patent applicationSer. No 09/334,400, the contents of which are hereby incorporated byreference as if recited in full herein.

[0131] In any event, as the bladder expands, it increases the pressureit exerts onto the dose bag 40. Preferably, the bladder is symmetricallyconfigured with discrete enclosed air (or gas or fluid) channels suchthat opposing channels contact opposing sides of the bag to facilitate aconstant and substantially equal distribution of pressure without theinflatable medium directly contacting the walls of the dose bag 40. Inaddition, instead of discrete channels 40C, the inflatable bag 40Bitself can be sealed and inflate around the enclosed dose bag.

[0132] Also, whenever more than one delivery mechanism is employed tointroduce polarized gas products to a subject, the MR imaging system 25can be configured to include an audible or visual alert to coordinatethe dispensing of the substances.

[0133]FIGS. 6, 7A and 7B illustrate another embodiment of a syringeinjection delivery system 75 according to the present invention. Asshown, the syringe 90 includes a plunger 92, a primary chamber 94,capillary stem 115, and LUER LOK flow member 116 with a valve 117. Asshown in FIG. 6, the LUER LOK flow member 116 is connected on one sidevia the valve 117 to a vacuum system 118. The valve configuration allowsa vacuum to be introduced to pull unwanted oxygen from the chamber toprepare the container prior to gas introduction therein.

[0134] In the past, high purity/high grade nitrogen has been used topurge the oxygen from the hyperpolarized gas containers to reducepolarization losses attributed thereto. According to a preferredembodiment of the present invention, CO₂ gas can be directed into thegas holding chamber and then removed via a vacuum introduced thereto ina “gas-evacuate” cleansing cycle. This CO₂ based gas-evacuate containerpreparation method can remove depolarizing oxygen from the containers.Further, even if residual traces of CO₂ remain in the chamber orpassages, any CO₂ injected with the hyperpolarized gas will be absorbedby the blood relatively quickly as noted above.

[0135] As the polarized gas contacts the primary chamber 94, the plunger92, and the walls of the capillary stem 115 and lumen (duringinjection), it is preferred that they be configured from a polarizationfriendly material. As used herein, the term “polarization friendlymaterial” means materials which reduce the contact induced decay orrelaxation associated therewith, such as materials which have reducedsolubility, permeability, or relaxivity values. Examples of suitablematerials will be described further below.

[0136] Accordingly, it is preferred that the primary chamber 94 and atleast the bottom primary surface 92B of the plunger (the gas contactingsurface) be configured from a gas-contacting material which has a lowrelaxivity for ¹²⁹Xe. This material can comprise a high purity metalwhich is substantially free of ferrous and paramagnetic impurities. Asshown in FIG. 7A, the bottom surface of the plunger 92B is formed of alow-relaxivity material and a second peripherally (circumferentially)positioned seal 92S. See co-pending U.S. patent application Ser. No.09/334,400 and 09/528,750, for a discussion of materials, containers,and gas delivery systems, the contents of which are hereby incorporatedby reference as if recited in full herein. The sealing material can alsobe coated with a polarization friendly material or formed of materialsand fillers with reduced depolarizing influence.

[0137] Exemplary materials for the interior surface of the primarychamber body and/or bottom surface of the plunger material (or other gascontacting surfaces such as capillary stems and conduits/catheters)includes certain polymers such as PE and nylon-6, and high purity glass(preferably high purity aluminosilicates) or quartz (or sol-gel coatedsurfaces (see e.g., PCT US98/16834 to Cates et al., entitled Sol-gelCoated Polarization Vessels), and high purity metallized surfaces(substantially free of ferrous and paramagnetic impurities)). If highpurity metal gas contacting surface materials are used, it is preferredthat the high purity metal surface be formed from one or more ofaluminum, gold, or silver. It is also preferred that any O-rings orseals used be coated with or formed from polarization-friendly materialsto protect the gas from contacting potentially depolarizing fillers andother materials used in many commercially available seals. Of course,the lumen 42L (FIG. 5) itself is also preferably formed such that atleast the gas-contacting surfaces are coated with a high purity metal.

[0138] As noted above, in one embodiment, the syringe 90 also includes acapillary stem 115 which is configured to separate the primary gaschamber 94 of the syringe 75 from the valve 117 (to reduce the exposureto same because outer components such as the valve 117 or conduit 41 canpotentially include depolarizing components). As such, the capillarystem 115 typically includes a reduced size diameter passage whichextends a distance between the chamber 94 and the LUER LOK flow member116, valve 117, and other components. Preferably, the capillary stem 115is formed of an aluminosilicate and is directly formed onto the end ofthe primary chamber 94. It is also preferred that the capillary stem 115is sized with a length which is at least about 10% the length of theprimary chamber, and more preferably at least 20% the length of theprimary chamber. For example, for a 10 ml syringe having a chamberlength of about 6 cm, the capillary stem has a corresponding length ofabout 6 mm. Of course, other configurations can also be used and thepresent invention is not considered to be limited thereto. For example,optimal or improved capillary stem sizing methods are discussed furtherbelow.

[0139] In one embodiment, to obtain about a relatively long T₁, thecontainer 100 includes a primary gas holding chamber which has a chambervolume which is substantially larger than the volume associated with thecapillary stem 115 (the chamber volume is preferably at least an orderof magnitude greater volume than the capillary stem volume). In thisembodiment, the capillary stem is configured with a length which isabout 6.9 cm. One may also configure the radius of the stem such that isat, or less than, about 0.3 cm.

[0140] Thus, in producing the injectable product container, the syringe75 can also be connected to the CO₂ source in conjunction with thevacuum source (or separately) to direct CO₂ gas into the syringe alongthe passage 115P in the capillary stem 115 so as to run a series ofseveral gas/evacuation or purge cycles to remove the oxygen and cleanthe chamber and capillary stem 115. The gas-evacuation preparationmethod will be discussed further below.

[0141] After the gas-evacuate cycle (or purge/pump cycles) the chamber94 can be finally evacuated and the valve 117 in preparation for fillingwith the hyperpolarized ¹²⁹Xe gas. Of course, the hyperpolarized gas canbe directed into the syringe chamber 94 at a later time or at a timeproximate to the evacuation step. In any event, once the desired volumeof gas is directed into the syringe 75, the valve 117 can be closed andthe syringe 75 transported to the patient. A catheter 42 can bepositioned and the lumen inserted into the patient in advance ofengaging the syringe to the conduit and opening the LUER LOK flow member116 to release the gas in to the in situ catheter 42 to deliver the gasat the appropriate time.

[0142]FIGS. 8A and 8B illustrate yet another system for controlling/andor dispensing hyperpolarized gas to a subject. FIG. 8A illustrates acontainer 100 with a primary valve 110, a primary gas holding chamber112, a capillary stem 115, and an expandable member 120. The primaryvalve 110 moves forward and rearward in response to rotation of the knob110R to open and close the passage defined by the capillary stem 115from the first port 116. A second entry port 125 is configured opposingthe capillary stem 115 in fluid communication with the primary gaschamber 112. Preferably, a secondary valve 130 operates to open andclose the second entry port 125. The expandable member 120 expands intothe primary chamber 112 when the valve 130 is opened and fluid isintroduced into the second entry port 125. The degree of expansion ofthe expandable member 120 corresponds to the quantity of fluidintroduced through the second port 125. A liquid, gas, or mixturethereof can be used to expand the expandable member 120.

[0143] In one embodiment, the expandable member 120 defines a barrierbetween the polarized gas and the expansion medium; the expansion mediumdoes not directly contact the polarized gas. Any suitable liquid or gascan be used as the expansion medium, and for thin barriers which mayallow the medium to travel therethrough, nitrogen or deoxygenated water,or other substantially non-depolarizing fluids can be used as theexpansion medium. In addition, because the expandable member doescontact the polarized gas, it is preferred that it be formed of apolarization friendly (low relaxivity and low solubility) material forthe polarized gas held therein. For example, a material such as LDPE ordeuterated HDPE, or more preferably a high purity non-magnetic metal andthe like, or other low-relaxivity material which has a low permeabilityfor the hyperpolarized gas held in the chamber may be employed. Seeco-pending patent application Ser. Nos. 09/163,721 and 09/334,400. Thecontents of these documents are hereby incorporated by reference as ifrecited in full herein.

[0144] As shown in FIG. 8B, after filling the container 100 at a fillsite with a desired quantity of hyperpolarized gas such as ¹²⁹Xe throughthe first entry port 116, an injection means such as a matable conduitor chamber with a direct inject needle/lumen, catheter or IV needle 119,42L is connected to the first entry port 116. In position, as shown thecontainer 100 can be oriented on its side so that the length of thedelivery or polarized gas dispensing path “L” away from the container100 can be reduced to reduce the potential exposure of the gas tocontaminants as it travels therethrough. In the embodiment illustrated,a controller 22 directs an air compressor 47 to inflate the expandablemember at a predetermined rate (preferably a constant rate). The primaryvalve 110 is opened and the polarized gas is allowed to exit the firstentry port 116 at a controlled rate into the injection path and into thelumen 42L. In addition, the capillary stem 115 of the container ispreferably configured such that once the gas is captured in the primarychamber 112, a major portion of the hyperpolarized gas in the containeris isolated away from potentially depolarizing components (such asfittings, valves, and the like) during transport and/or storage as notedabove. Of course, other flow control configurations can also beemployed. For example, filling a container having a valve in fluidcommunication with tubing to about 2 atm with polarized ¹²⁹Xe. The valvecan be opened and the pressure difference directs the gas into thetubing out of the container. Of course, over time, the flow rate due tothe pressure differential will drop.

[0145] The capillary stem 115 can be formed as an integral part of thevalve member 110 or as a separate component. For example, the valve 110can include a body portion formed of glass such as Pyrex® or the like,and the capillary stem 115 can be directly formed onto an end portion ofthe valve 110. Alternatively, the capillary stem 115 can also be formedfrom a glass such as Pyrex® or an aluminosilicate, or other material toextend therefrom as a continuous body co-joined or fused to the lowerportion of the valve 110. The valve illustrated in FIGS. 8A and 8Bincludes a plug portion 110P which longitudinally translates to engagewith the lower nozzle end of the valve chamber 110N to close the flowpath when the valve is in the closed position. In the reverse, the valveplug 110 p moves away from the nozzle end 110 n to allow the gas to flowthrough the capillary stem 115 and the and in (or out) the entry port116.

[0146] Operationally, still referring to FIG. 8B, the capillary stem 115is configured such that a major portion of the hyperpolarized gas, oncein the chamber 112, remains therein when the valve 110 is closed. Thatis, the dimensions and shape of the capillary stem 115 are such thatdiffusion of the hyperpolarized gas away from the container chamber 112is inhibited. Thus, the capillary stem 115 can reduce the amount ofexposure for a major portion of the hyperpolarized gas with the valve110 and any potentially depolarizing components operably associatedtherewith. In addition, the capillary stem 115 also provides a portionof the gas flow path 22 f therethrough. As such, the capillary stem 115includes an internal passage which is preferably sized and configured ina manner which inhibits the flow of gas from the chamber 112 duringstorage or transport while also allowing the gas to exit the chamber 112at its ultimate destination (injection site) without undue orsignificant impedance.

[0147] In sizing a capillary stem (which can be employed with any typeof container housing hyperpolarized noble gas ( such as that shown inFIGS. 6 or 8A or otherwise)) to optimize the T₁ of the ¹²⁹Xe gas heldtherein, the following analysis can be used. Generally stated, T₁ can berepresented by the following equation:$T_{1} \approx \frac{V_{main}l_{c}}{2\pi \quad {R_{c}( {{DR}_{c} + {\psi \quad l_{c}^{2}}} )}}$

[0148] Reviewing the equation, it will be appreciated that as T₁→∞ asR_(c)→0. Thus, the “best” capillary radius is none at all. However, thisis not practicable. Typically, a certain basic or minimum capillaryradius is needed, i.e., sufficiently sized, in order to allow gas toflow in and out of the capillary and for the main chamber to besuccessfully evacuated. In addition, some design limit can be placed onthe “gas conductivity” of the capillary. This aspect will be discussedfurther below. In any case, once a capillary radius or width has beenchosen, the equation above can be used to determine an improved or“optimal” capillary length by differentiating the equation and settingit equal to zero. (Of course, the equations below can be used in thereverse to establish a desired radius based on a particular length).$\frac{T_{1}}{l_{c}} = 0$

[0149] This yields a solution for the optimal capillary lengthrepresented by the following equation:$l_{c} = \sqrt{\frac{{DR}_{c}}{\psi}}$

[0150] Note that this solution for l_(c) sets the diffusion component ofrelaxation in the capillary equal to the surface-induced component ofrelaxation. Since the assumption of infinite depolarization rate at theend of the capillary is probably overstated, one can adjust (reduce) thedetermined or calculated capillary length a little shorter.

[0151] In order to calculate optimal capillary lengths, relaxivityvalues or estimates are needed. As a simple estimate, one can considerthat an 180 cc spherical chamber of GE180 glass has a relaxation timesof about 40 hr for ³He and about 2 hr for ¹²⁹Xe. Knowing therelationship of“A/V-3/R” for a sphere, one can determine the relaxivityψ of GE180 glass for both gases. The diffusion coefficients are notedfor reference below. Gas T₁ ψ D ³He 40 hr 8.1 × 10⁻⁶ cm/s  2.05 cm²/s¹²⁹Xe  2 hr 1.7 × 10⁻⁴ cm/s 0.065 cm²/s

[0152] The table above illustrates that optimal capillary lengths willbe very different for ¹²⁹Xe with its smaller diffusion coefficient andmuch larger relaxivity than ³He. Thus, this is preferably taken intoaccount when designing the ¹²⁹Xe capillary stem. For example, if weassume a 1 mm capillary diameter, and use the values of relaxivityabove, one can find the following: D I_(opt) ³He  2.05 cm²/s 111 cm¹²⁹Xe 0.065 cm²/s  4.4 cm

[0153] Thus, for a ¹²⁹Xe syringe whose main chamber volume is about 20cm³, using a 4.4 cm capillary of 1 mm diameter can yield a capillarycontribution to relaxation of T₁≈12 hr. Double the capillary lengthwould yield a T₁ of about 9.5 hr, and half the capillary length wouldyield a T₁ of about 9.5 hr. FIG. 11 is a graph which illustrates anoptimum capillary length (if one employs a stem with a length which iseither larger or smaller than the optimal length, the T₁ is reduced overthe T₁ obtainable at the optimal length)

[0154] In a preferred embodiment, the container 100 body (and thesyringe body 94) is substantially formed from quartz glass gascontacting surfaces (high purity Si—O₂), Pyrex®, aluminosilicate glassessuch as GE180, CORNING 1720 or other long T₁ life silica based material.Transition glasses may be used to make a transition between glassmaterials having different thermal expansion coefficients. For example,for containers using multiple types of glass such as Pyrex®, body andGE180 stem or other portion, a transition glass (such as Uranium glass(typically about 35% 235 U)) can be employed to join the two glasses andform the container. A suitable glass valve is available from KimbleKontes Valves located in Vineland, N.J.

[0155] As is shown in FIGS. 7B and 8B, it is also preferred that a smallexcitation NMR coil 230 be positioned onto the container primary body94, 112 and operably engaged with the NMR image system 26 via atransmit/receive line 26T. The NMR excitation coil 230 can be in theflow path as shown or located on the side, proximate the exit path(shown as 230 a in FIG. 8B). This can allow a calibration measurement tobe initiated just prior to dispensing the gas to the subject. Of course,the NMR coil 230 can be positioned in other locations along the body ofthe container, and the calibration measurement can be taken prior toengagement with the controller 22 or the like. In any event, theinjection dose containers of the present invention (such as item 100 inFIG. 8A, items 35 and 40 in FIG. 2, and item 75 in FIG. 6) can allowtransport of ¹²⁹Xe to the hospital from remote locations (by providingimproved T₁'s) and can also enable calibration of the gaseous dosagejust prior to injection.

[0156] FIGS. 8C-81 illustrate alternate embodiments of an injectiondevice according to the present invention. As shown in FIG. 8C, aninjector head 300 having a plurality of gas orifices 310 facing in theflow direction can be used to administer the hyperpolarized ¹²⁹Xe gas tothe subject. The orifices 310 are sized and configured so as to dispensethe gas into the subject in a fine dispersion. In certain embodiments,in operation, the injector head 300 is configured to dispense a finedispersion or spray of gas having microbubble sizes under about 50 μm,and preferably substantially between about 0.5-10 μm.

[0157] In certain embodiments, the orifices 310 may have an aperturewidth or diameter of about 1 nm-50 μm, and preferably a width which isabout 10 μm or less such as between about 10 nm-10 μm, between about0.01-10 μm, or between about 0.01-1 μm to increase the surface area (anddecrease the volume) of the bubbles corresponding to the administeredgas as it enters the tissue, blood, or selected region of the body.Decreasing the volume and increasing the surface area of the bubbles asthey enter the blood stream may promote increased rates of ¹²⁹Xedissolution into the blood (while inhibiting aggregation intoundesirable large bubble sizes). A discussion on certain aspects ofnanojet configurations can be found in Moseler et al, Formation,Stability, and Breakup of Nanojets, Science, Vol. 289, No. 5482, pp.1165-1169 (Aug. 18, 2000); the contents of which are hereby incorporatedby reference as if recited in full herein.

[0158] The injector head 300 can be formed in or inserted into a distalend portion of an intravenous or intrarterial catheter 340 as shown inFIG. 8D. The injector head 300 may also be positioned at other locationsin the hyperpolarized gas flow path (such as at a position with isexternal of the body upstream of the entry point into the subject in thecatheter or in a conduit connected thereto).

[0159] As shown in FIG. 8D, the injector head 300 is in fluidcommunication with a source of hyperpolarized ¹²⁹Xe 350 and a pressuresource 375. In operation, a constant or variable pressure forces thehyperpolarized ¹²⁹Xe to flow through the injector head 300 and out ofthe orifices 310 to form a gaseous dispersion at a point proximate theentry site of the subject. The constant or variable pressure can begenerated with a pressure sufficient to provide a gas flow ratesufficient to create the desired bubble size. Typical flow rates are asdescribed above, such as about 3 cc/s or less (which in certainembodiments administers the gas dose of about 60 cc's over a 20 secondinjection period). The variable pressure can be provided to generate apulsatile flow (either via a step function operation or a ramped orgradual variation (increase and/or decrease) over time). The pressuresource 375 may be a power injector device, such as those which are wellknown to those of skill in the art. In operation, a rapid, controlled(pressure and volume) injection of gaseous hyperpolarized ¹²⁹Xe can beadministered to the subject.

[0160] The injector head 300 can be formed into a conduit disposedbetween the (intravenous or intrarterial) catheter which is configuredto pierce the skin of the subject or may be positioned or formed in thecatheter itself as noted above.

[0161] In certain embodiments, the temperature of the hyperpolarized gascan be adjusted (heated or cooled) prior to ejection through theinjector head 300. If cooled, the temperature should be sufficient toassure that the gas remains in the gaseous state at injection. Incertain embodiments, the hyperpolarized xenon gas can be heated so thatit is at least 70 degrees F., and preferably in the range of about98.6-105 degrees F., as it travels through the injector head orifices310. The hyperpolarized gas can be heated by exposing the captured gasto an elevated temperature as it travels along the flow path or bypre-heating a container holding the supply of ¹²⁹Xe prior to releasingthe hyperpolarized gas into the administration exit flow path.Alternatively, or additionally, the injector head 300 may also beheated. In certain embodiments, heating methods and devices are selectedso that, in operation, they do not substantially negatively impact thepolarization of the gas (a liquid heated immersion bath for the ¹²⁹Xesource container or a supplemental heating container positioned in theflow path, solar or light energy directed to the polarized gas, aflowable heated gas which is directed over the outer surface of theenclosed gas flow path, etc.).

[0162] As shown in FIGS. 8G and 8H, the injector head 300 can beconfigured with a convergent nozzle configuration. FIG. 8G illustratesthat the injector head 300 itself can have a convergent nozzle profile301 to direct the gas from the flow path upstream thereof and into tothe enclosed nozzle region and out of the orifices 310 positioned at theconvergent end thereof. FIG. 8H illustrates that the orifices 310 can beconfigured in the injector head 300 so that the individual orifices eachdefine a convergent nozzle, identified as a convergent nozzle orifice310 cn (decreases in area from the proximal end to the distal end alongthe axial direction of flow). Of course the injector head 300 mayincorporate both features, convergent nozzle orifices 310 cn with aconvergent profile 301.

[0163]FIG. 81 illustrates that the injector head 300 may includeconstant area orifices 310 ca as well as convergent area nozzle orifices310 cn. In other embodiments, the injector head 300 may be configuredwith a constant area body and/or the orifices 310 may be formed as onlyconstant area orifices 310 ca without convergent area nozzle orifices310 cn (not shown).

[0164]FIG. 8G illustrates that the administration can be performed suchthat an additive can be mixed in situ with the polarized ¹²⁹Xe to helpform the fine dispersion formulation at ejection from the injector head300. The additive is a pharmaceutical grade biocompatible substancewhich is substantially non-depolarizing to the polarized ¹²⁹Xe gas.Examples of suitable substances may include blood, plasma, lipids, gasessuch as CO₂ or noble gases including non-hyperpolarized xenon,deuterated substances, or commercially available biomedical contrastagents. See e.g., 60/014,321 and WO 97/37239 to Pines et al. and WO99/52428 to Johnson et al., the contents of which are herebyincorporated by reference as if recited in full herein.

[0165] In certain embodiments, as shown in FIG. 8F, the additive can bean emulsifier which is added to a mixing chamber 375 positioned upstreamof the injector head 300 so that the emulsifier is mixed with thehyperpolarized gas to form an emulsified composition of gas as it isextruded or travels through the orifices 310 of the injector head 300.The emulsifer material can be selected such that it is flowable and isable to encapsulate the hyperpolarized gas to promote surfacestabilization or to promote the fine dispersion of hyperpolarized gasinto the blood. As shown in FIG. 8F, the catheter or conduit 340 can beconfigured with two separate flow channels 353, 354, which end into theenclosed mixing chamber 375 upstream of the injector head 300. Themixing chamber 375 may include baffles, a venturi, or other mixercomponents to promote the intermixing of the hyperpolarized gas with theemulsifier (or other additive).

[0166] As shown in FIG. 8E, the hyperpolarized gas flow path 353 as wellas the additive flow path 354, may include a flow meter 355,455,respectively, or other flow or volume measurement device. In certainembodiments, the additive is controlled so that a substantially lesseramount of additive is used in comparison to the hyperpolarized gas(i.e., 25-40% less than the volume of gaseous polarized ¹²⁹Xe). It isnoted that the injection system and components described herein may alsobe suitable for dispensing other gases or agents such as hyperpolarized³He.

[0167] The gas contacting surfaces of the injector head 300 can beformed of or coated with suitable materials to inhibit thedepolarization of the gas as it travels therethrough. Examples ofsuitable materials include, but are not limited to, alumminosilicateglass, certain polymer materials or metallic materials or othermaterials as described herein. Surface coatings, such as a sputtercoating of a non-depolarizing material of high purity silver oraluminum. The relaxivity of high purity aluminum for ¹²⁹Xe has beenrecently measured to be about 0.00225 cm/min. Metals other than aluminumwhich can be used include indium, gold, zinc, tin, copper, bismuth,silver, niobium, and oxides thereof. Preferably, “high purity” metalsare employed (i.e., metals which are substantially free of paramagneticor ferrous impurities) because even minute amounts of undesirablematerials or contaminants may degrade the surface. Preferably, the metalis chosen such that it is well below 1 ppm in ferrous or paramagneticimpurity content.

[0168] As noted above, because paramagnetic oxygen can be destructive tothe polarization of the polarized gas, it is preferred that any syringe,dose bags or other gas containers or gas contacting components such asconduit, catheters, injector heads, mixing chambers, and the like, bepreconditioned, i.e., carefully cleaned of magnetic impurities andpurged of paramagnetic oxygen. That is, any gas contacting containers orsurfaces are processed to reduce or remove the paramagnetic gases suchas oxygen from within the chamber and container walls.

[0169] It is preferred that the containers be prepared as brieflydiscussed above. For containers made with rigid substrates, such asPyrex®, UHV vacuum pumps can be connected to the container to extractthe oxygen. However, a roughing pump can also be used which is typicallycheaper and easier than the UHV vacuum pump based process for bothresilient and non-resilient containers. Preferably, for resilient dosebags, the bags are processed with several purge/pump cycles, e.g.,pumping at or below 20 mtorr for one minute, and then directing cleanbuffer gas (such as CO₂) into the container at a pressure of about oneatm or until the bag is substantially inflated. The oxygen partialpressure is then reduced in the container. This can be done with avacuum but it is preferred that it be done with CO₂ (at least for theinjection containers). Once the oxygen realizes the partial pressureimbalance across the container walls, it will outgas to re-establishequilibrium. Stated differently, the oxygen in the container walls isoutgassed by decreasing the partial pressure inside the containerchamber. Typical oxygen solubilities are on the order of 0.01-0.05;thus, 95-99% of the oxygen trapped in the walls will convert to a gasphase. Prior to use or filling, the container is evacuated, thusharmlessly removing the gaseous oxygen. Unlike conventional rigidcontainers, polymer bag containers can continue to outgas (trapped gasescan migrate to the chamber because of pressure differentials between theouter surface and the inner surface) even after the initial purge andpump cycles. Thus, care should be taken to reduce this behaviorespecially when the final filling is not temporally performed near thepreconditioning of the container. Preferably, for bags or resilientcontainers, a quantity of clean filler gas is directed into the bag (tosubstantially equalize the pressure between the chamber and ambientconditions) and sealed for storage in order to reduce the amount offurther outgassing that may occur when the bag is stored and exposed toambient conditions. This should substantially stabilize or decrease anyfurther outgassing of the polymer or container wall materials. In anyevent, the filler gas is preferably removed (evacuated) prior to finalfilling with the hyperpolarized gas.

[0170] It is also preferred that the container, syringe, conduit,catheter, injector device, dose bag, or the like, be sterilized prior tointroducing the hyperpolarized product therein. As used herein the term“sterilized” includes cleaning containers and contact surfaces such thatthe container is sufficiently clean to inhibit contamination of theproduct such that it is suitable for medical and medicinal purposes. Inthis way, the sterilized container allows for a substantially sterileand non-toxic hyperpolarized product to be delivered for in vivointroduction into the patient. Suitable sterilization and cleaningmethods are well known to those of skill in the art.

[0171] The injectable dose is configured as a smaller quantity gas phaseproduct than the inhalation dose as described above. The inhalation dosecan be mixed with other inert gases such as nitrogen or otherbiocompatible fluids to help disperse or atomize the gas in the body(typically in the blood stream). As described above, subsequent toinhalation, at least a portion of the inhaled polarized gas enters intoa dissolved state which enters the pulmonary arterial vasculature,including the boundary tissue, cells, membranes, and pulmonary bloodvessels. Thus, a substantial amount of the dissolved polarized ¹²⁹Xeultimately enters the blood stream with an associated perfusion rate andcycles to the left atrium via the pulmonary vein, then to the leftventricle and out through the aorta.

[0172] Dissolved phase ¹²⁹Xe can have a relatively short relaxationtime, T₁, generally thought to be due to the presence of oxygen and dueto paramagnetic deoxyhemoglobin in the blood compared to ¹²⁹Xe whichremains in the gaseous phase in the blood. In addition, even within asubject's own circulatory system different T₁'s will be exhibited. Forexample, T₁ for substantially fully oxygenated human cell membranes (thesystemic arterial portion) will have a longer T₁ than the systemicvenous portion. That is, the T₁ of the polarized gas in the systemicvenous portion will be less than the T₁ of the polarized gas in thesystemic artery portion of the circulatory system which is moreoxygenated than the systemic venous portion.

[0173] As is also known to those of skill in the art, the polarized¹²⁹Xe also has an associated transverse relaxation time, T₂*. In thebloodstream, the non-dissolved as well as the dissolved phase can haveassociated T₂* which is acceptable to obtain signal or images. Indeed,the ¹²⁹Xe remaining as a gas in human blood will tend to exhibit longerT₂*'s than that dissolved in human blood. Taking advantage of thischaracteristic, particularly for gas-phase based imaging (especially forT₂*'s which are greater than at least about 30 milliseconds), multi-echoacquisition methods may be used. As will be appreciated by those ofskill in the art, examples of suitable multi-echo methods include EchoPlanar Imaging (“EPI”), Rapid Acquisition with Relaxation Enhancement(“RARE”), FSE (“Fast Spin Echo”), Gradient Recalled Echoes (“GRE”), andBEST. Examples of some suitable pulse sequences can be found in anarticle by John P. Mugler, III, entitled Gradient-Echo MR Imaging, RSNACategorical Course in Physics: The Basic Physics of MR Imaging, 1997;71-88. For example, the article illustrates an example of a standardsingle RF spin-echo pulse sequence with a 90 degree excitation pulse anda 180 degree refocusing pulse. G_(P) is a phase-encoded gradient, G_(R)is the readout gradient, G_(S) is the section-select gradient, and RF isthe radio frequency. The article also illustrates a Gradient RecalledEcho pulse sequence (GRE) with a flip angle α and a Rapid Acquisitionwith Relaxation Enhancement (RARE) pulse sequence as well as a singleshot Echo Planar Imaging (EPI) pulse sequence with gradient recalledechoes.

[0174]FIG. 9 is a graph of one potential timing sequence which may beused and shows the delivery time of the injected gas (t_(inj)) and a MRIpulse imaging sequence according to one embodiment of the presentinvention. The imaging sequence illustrates a relatively long injectiontime during which a plurality of short small flip angle (below about 45degrees, and more preferably below about 20 degrees) excitation pulsesare directed at the target region. The exciation pulses begin shortlyafter the start of the injection (t-t₁) and end shortly after theinjection ends (t_(end image)). In any case, the end of clinicallyuseful signal generation associated with the injected hyperpolarized gaswhich is suitable for imaging is typically about 25 seconds after thegas injection has ended, as the polarization of the gas has effectivelydecayed by this time. Of course, the choice of which flip angle andimaging procedure to use can depend on how many echoes can be done andhow many phase encodes steps are pursued. For single echo acquisitionsand increased (or optimal) SNR, having 128 phase encodes, a flip angleof about 5.1 degrees can be used.

[0175] It will be appreciated that at high magnetic field strength, itis possible to obtain increased image signal strength based on thedissolved phase direct injection polarized gas as well as the signalstrength from gas phase ventilation in the lung. This can provideimproved signal image resolution associated with the injected gas. Itwill also be appreciated that there will be separate and distinctlyresolvable excitation resonances associated with the (dissolved) versusventilation (gas) imaging data signals. In contrast, at low magneticfield strengths, the separate resonances distinct at high fields, mayoverlap to provide an apparent increased image signal strengthassociated with both the dissolved and gas phase polarization.

[0176] Preferably, particularly for longer injection times (a deliveryadministered over a time which is greater than about 2.5 seconds), oneor more small flip angle pulses can be employed to excite the polarizedgas in the target region (such as the vasculature) to selectivelydestroy the polarization in a more localized image acquisition. As usedherein, the term “small angle” means less than about 45 degrees.

[0177] Preferably, the gas injection sized quantities of hyperpolarized¹²⁹Xe are formulated as istopically enriched polarization gaseousproducts.

EXAMPLES

[0178] FIGS. 10A-10P are graphs of NMR spectra obtained about every 0.5seconds with a 20 degree excitation pulse via a whole body imager basedon about a 3 cc polarized ¹²⁹Xe gas injection into the vein of a rabbit(total of elapsed time from FIG. 10A to 10P being about 8 seconds). Therabbit survived the experiment. The graphs illustrate that the gasremained substantially in the gas phase (substantially non-dissolved orinsoluble in the bloodstream as it traveled through the bloodstreamduring the image acquisition). The signal strength at 8 seconds (FIG.10P) being about 0.65 that of the original signal (FIG. 10A). The rabbitwas placed in a whole body imager so that the exact location of thesignal within the rabbit's body is not disclosed in the spectra. It isnoted that a large quantity of the injected gas remained in the gasphase upon injection, most likely due to the size of the lumen used,about 0.5 mm.

[0179] It is also notable that the T₁ of the gas in the blood isrelatively long, at least about 20 seconds (for comparison, the T₁ ofgas dissolved in blood is typically less than 20 seconds, such as about4-6 seconds depending on oxygenation).

[0180] In summary, it is anticipated that diagnostic images can beobtained according to the present invention for desired target organs orsystems, such as but not limited to, the kidneys, the brain or craniumregion for cerebral assessment (grey/white matter/blood), the liver,spleen, intestines, lower extremity blood circulation, tumor assessment(oxygen tension) and coronary artery restrictions/blood flow and otherregions of interest.

[0181] The foregoing is illustrative of the present invention and is notto be construed as limiting thereof. Although a few exemplaryembodiments of this invention have been described, those skilled in theart will readily appreciate that many modifications are possible in theexemplary embodiments without materially departing from the novelteachings and advantages of this invention. Accordingly, all suchmodifications are intended to be included within the scope of thisinvention as defined in the claims. In the claims, means-plus-functionclauses are intended to cover the structures described herein asperforming the recited function and not only structural equivalents butalso equivalent structures. Therefore, it is to be understood that theforegoing is illustrative of the present invention and is not to beconstrued as limited to the specific embodiments disclosed, and thatmodifications to the disclosed embodiments, as well as otherembodiments, are intended to be included within the scope of theappended claims. The invention is defined by the following claims, withequivalents of the claims to be included therein.

That which is claimed is:
 1. A method of screening for the presence of apulmonary embolism, comprising the steps of: positioning a subjecthaving a pulmonary region and a blood circulation path including veinsand arteries in an NMR system, the subject's pulmonary region havingpulmonary veins and pulmonary arteries and associated vasculaturedefining a pulmonary portion of the circulation path; injecting a firstquantity of polarized gaseous ¹²⁹Xe directly into at least one vein ofthe subject; obtaining NMR signal data associated with the polarized¹²⁹Xe in the pulmonary region of the subject, the signal data includinginformation corresponding to the polarized gas introduced in saidinjecting step; generating an MRI image having spatially coded visualrepresentation of the NMR signal data; and identifying the presence ofat least one condition of blockage, restriction, abnormality, andsubstantially unobstructed free passage of the pulmonary circulationpath.
 2. A method according to claim 1, wherein the quantity of injectedpolarized gaseous ¹²⁹Xe is less than about 100 cubic centimeters.
 3. Amethod according to claim 1, further comprising the step of controllingthe rate of injection to less than about 3 cc/s at which the injectingstep is performed to thereby control the delivery rate of the polarizedgaseous ¹²⁹Xe into the vein.
 4. A method according to claim 2, whereinsaid injected quantity is less than about 20 cc's.
 5. A method accordingto claim 1, wherein said identifying step includes determining based onsaid injecting into the vein step whether the pulmonary circulatory pathis blocked or restricted based on the presence of polarized ¹²⁹Xe in thepulmonary arteries.
 6. A method according to claim 1, wherein saidobtaining step includes obtaining NMR signal data associated with thepresence of gaseous phase polarized ¹²⁹Xe in the lungs, the image signalintensity of which corresponds to the restriction, blockage or freepassage of the pulmonary circulatory path.
 7. A method according toclaim 6, wherein after said injection step, a portion of the injectedpolarized gaseous polarized ¹²⁹Xe travels along a portion of thepulmonary circulation path and subsequently enters the lung cavity in aquantity sufficient to provide NMR data with an associated signalintensity, a decreased signal intensity corresponding to the presence ofa blockage or restriction in the pulmonary circulation path.
 8. A methodaccording to claim 1, further comprising the step of administering theinjection such that the gaseous polarized ¹²⁹Xe substantially dissolvesinto the vasculature proximate to the injection site.
 9. A methodaccording to claim 8, wherein the controlled injection rate is less thanabout 2 cc/s.
 10. A method according to claim 1, wherein said injectingstep is carried out such that a major portion of the gaseous polarized¹²⁹Xe remains substantially as a gas in the bloodstream and exhibits aT₁ in the bloodstream which is greater than about 8 seconds.
 11. Amethod according to claim 1, wherein said NMR signal data obtaining stepis performed in a low magnetic field, wherein the field strength is lessthan about 0.5 T.
 12. A method according to claim 11, wherein the signalpeaks associated with the ¹²⁹Xe in plasma and the ¹²⁹Xe in red bloodcells overlap to increase signal intensity associated therewith.
 13. Amethod according to claim 1, further comprising the step of introducinga second quantity of a polarized gas to a subject via inhalation duringa single imaging session.
 14. A method according to claim 1, whereinsaid injection step is carried out intravenously.
 15. A method accordingto claim 14, wherein said injection step is carried out via a hypodermicsyringe, and wherein said syringe includes gas contacting surfaces whichare formed from polarization friendly materials.
 16. A method accordingto claim 13, wherein the second polarized gas comprises ¹²⁹Xe.
 17. Amethod according to claim 16, wherein said obtaining step includes thesteps of: exciting and receiving signal data associated with both thefirst and second quantities of ¹²⁹Xe with a single transmit/receiveexcitation coil; and analyzing the NMR signal data associated with saidexciting and receiving step in a way which distinguishes gaseous phase¹²⁹Xe from the dissolved ¹²⁹Xe in said image generation step.
 18. Amethod according to claim 1, wherein said injection comprises multiplesequential injections thereby allowing for multi-shot MR imaging.
 19. Amethod according to claim 15, wherein the first quantity of polarized¹²⁹Xe is isotopically enriched.
 20. A method according to claim 1,wherein said injected quantity of ¹²⁹Xe includes a small amount of CO₂therewith.
 21. A method according to claim 1, further comprising thestep of introducing a quantity of surfactant into a subject proximate tothe injection site of the ¹²⁹Xe.
 22. A method according to claim 1,further comprising the step of expelling the ¹²⁹Xe gas from a containerinto the subject during said injecting step such that the formation oflarge ¹²⁹Xe gas bubbles are inhibited during said injecting step.
 23. Amethod according to claim 22, wherein said expelling step configures thebubbles in sizes which are less than about 10 microns in diameter.
 24. Amethod of enhancing the resolution of MRI-based medical images,comprising the steps of: injecting directly into an injection siteassociated with a subject a first quantity of polarized ¹²⁹Xe in gaseousform during an NMR imaging session; delivering a second quantity ofpolarized gas product to the subject within the same imaging session assaid injecting step, the second quantity being larger than the firstquantity; and generating an MRI image corresponding to the excitation ofthe first and second quantities of polarized gas introduced in saidinjecting and delivering steps.
 25. A method according to claim 24,further comprising the step of introducing a surfactant to thevasculature of a subject such that the surfactant resides proximate tothe injected ¹²⁹Xe.
 26. A method according to claim 25, wherein theinjection site is associated with a portion of the systemic venouspulmonary vasculature.
 27. A method according to claim 25, wherein theinjection site is associated with a portion of the systemic arterialpulmonary vasculature.
 28. A method according to claim 24, wherein saidinjecting step is performed by injecting into a vein.
 29. A methodaccording to claim 23, wherein said delivering step is performed byinjecting to an artery.
 30. A method according to claim 24, furthercomprising the step of expelling the polarized ¹²⁹Xe gas from acontainer into the subject during said injecting step such that theformation of large ¹²⁹Xe gas bubbles are inhibited during said injectingstep.
 31. A method according to claim 30, wherein said expelling stepforms the ¹²⁹Xe into bubbles in sizes which are less than about 10microns in diameter.
 32. A method according to claim 24, wherein saiddelivering step is performed by injecting the second quantity ofhyperpolarized gas as a liquid into the subject.
 33. A method accordingto claim 24, wherein said delivering step is performed by injecting thesecond quantity of hyperpolarized gas as a gas.
 34. A method accordingto claim 24, wherein said delivering step comprises the steps ofintroducing via inhalation to the lungs the second quantity ofhyperpolarized gas wherein a portion of the inhaled gas subsequentlyenters into pulmonary venous vasculature via perfusion uptake into thebloodstream and then subsequently enters the pulmonary vein(s).
 35. Amethod according to claim 24, wherein said delivering step is carriedout via a second injecting step and wherein the first quantity is lessthan about 20 cc's, and wherein the second quantity is less than about100 cc's.
 36. A method according to claim 24, further comprising thestep of administering the first quantity of polarized ¹²⁹Xe gas suchthat it substantially dissolves into the vasculature proximate to theinjection site.
 37. A method according to claim 24, further comprisingthe step of administering the first quantity of polarized ¹²⁹Xe gas suchthat it remains substantially non-dissolved in the bloodstream andexhibits a T₁ of at least eight seconds therein.
 38. A method accordingto claim 24, further comprising the step of processing NMR signal dataassociated with both said injecting and delivering steps in a mannerwhich distinguishes NMR signal information corresponding to gas phaseversus dissolved gas signal information in said MRI image generatingstep.
 39. A method according to claim 24, further comprising the step ofperforming said generating step at a low magnetic field strength andacquiring the NMR signal data so that the signal peaks associated withthe hyperpolarized ¹²⁹Xe in the red blood cells and plasma of the bloodoverlap.
 40. A method according to claim 34, wherein said administeringstep is carried out at an injection rate which is less than about 2cc/s.
 41. A method according to claim 24, wherein said injected firstquantity of ¹²⁹Xe gas comprises trace amounts of CO₂.
 42. A method ofobtaining diagnostic images of the cranial region, comprising the stepsof: injecting less than about 5 cc's of ¹²⁹Xe polarized gas into aninjection site in a carotid artery; dissolving said polarized ¹²⁹Xe gasinto the vasculature proximate to the injection site; and generating anNMR image having signal intensity associated with the NMR excitation ofthe dissolved injected ¹²⁹Xe.
 43. A method according to claim 42,wherein said injecting step is performed in a manner which facilitatesthe dissolution of the gas in the vasculature proximate to the injectionsite.
 44. A method according to claim 41, wherein said injecting step iscarried out in a manner which inhibits the bubble size associated withthe injected ¹²⁹Xe from being larger than about 10 microns in diameter.45. A method according to claim 41, further comprising the step ofinjecting a quantity of a physiologically acceptable surfactant in vivosuch that it is directed proximate to the injection site.
 46. A methodof facilitating bubble dissipation associated with the injection ofpolarized gaseous ¹²⁹Xe, comprising the step of introducing in vivo aphysiologically acceptable surfactant temporally proximate to the invivo injection of a quantity of hyperpolarized gas.
 47. A method ofobtaining an MR image, comprising the steps of: injecting less thanabout 100 cc's of gaseous hyperpolarized ¹²⁹Xe in vivo into thevasculature of a mammalian subject; and generating a NMR signalcorresponding to the injected quantity of hyperpolarized ¹²⁹Xe gas. 48.A method according to claim 46, further comprising the step ofadministering the injection of the gas into the vasculature so that thegas is substantially dissolved into the vasculature proximate to theinjection site.
 49. A method according to claim 46, further comprisingthe step of administering the injection of the gas into the vasculatureso that the gas is substantially non-dissolved into the vasculatureproximate to the injection site.
 50. A method according to claim 47,wherein said injecting step is performed by injecting the hyperpolarized¹²⁹Xe into at least one predetermined injection site chosen from thegroup consisting of a carotid artery, a pulmonary artery, a hepaticartery, and a renal artery.
 51. A method according to claim 47, whereinsaid injecting step is performed by injecting the hyperpolarized ¹²⁹Xegas into at least one injection site chosen from the group consisting ofa vein in the arm, a jugular vein, a pulmonary vein, a hepatic vein, anda renal vein.
 52. A method according to claim 47, wherein said injectingstep is performed by injecting the hyperpolarized ¹²⁹Xe into at leasttwo different injection sites, the sites chosen from the groupconsisting of a carotid artery, a pulmonary artery, a hepatic artery, arenal artery, a vein in the arm, a jugular vein, a pulmonary vein, ahepatic vein, and a renal vein.
 53. A method according to claim 47,wherein said injecting step comprises serially injecting quantities of¹²⁹Xe gas during a predetermined imaging period to thereby allowmulti-shot imaging.
 54. A method according to claim 47, furthercomprising the step of injecting a quantity of a physiologicallyacceptable surfactant in vivo such that it is directed proximate to theinjected site.
 55. A method according to claim 47, wherein saidpredetermined injected quantity is less than about 20 cc's.
 56. A methodaccording to claim 47, wherein said injecting step is carried out in amanner which inhibits the bubble size associated with the injected ¹²⁹Xefrom being larger than about 10 microns in diameter.
 57. A methodaccording to claim 47, wherein said injected ¹²⁹Xe gas comprises traceamounts of CO₂.
 58. A method according to claim 47, wherein saidinjecting step comprises directing the hyperpolarized gaseous ¹²⁹Xethrough an intravenous catheter positioned in the vein of a subject. 59.A method according to claim 58, wherein said directing step comprisesdirecting the hyperpolarized gas through an injector head comprising aplurality of outlet flow orifices formed therein to disperse thehyperpolarized gas into the blood stream of the subject.
 60. A methodaccording to claim 59, further comprising the step of heating thehyperpolarized gas prior to said injecting step.
 61. A method accordingto claim 58, wherein the injector head includes at least one of aconvergent nozzle profile and convergent nozzle orifices.
 62. A methodaccording to claim 59, wherein said directing step comprises directingthe hyperpolarized gas such that it flows into a mixing chamber prior toexiting from the injection head orifices.
 63. A method according toclaim 58, further comprising the step of adding an emulsifier to thehyperpolarized gas in advance of the injecting step.
 64. A method ofevaluating the efficacy of targeted drug therapy, comprising the stepsof: delivering a quantity of a predetermined gene treatment preparationor pharmaceutical drug in vivo into a mammalian subject having a targetsite and a treatment condition; injecting a predetermined quantity ofgaseous phase hyperpolarized ¹²⁹Xe in vivo into a mammalian subject suchthat the hyperpolarized gas is delivered to the target site in gaseousor dissolved form; generating a NMR image or spectroscopic signal of thetarget site associated with the injected hyperpolarized ¹²⁹Xe gas; andevaluating the NMR image or spectroscopic signal to evaluate theefficacy of the gene treatment or drug on the treatment conditionadministered in said delivering step.
 65. A method according to claim64, further comprising the step of acquiring at least two sets of data,the data representing two temporally spaced apart points in time, toevaluate if the treatment condition is influenced by the drug or genetherapy introduced in said delivering step.
 66. A method according toclaim 64, further comprising the step of evaluating whether the drug isproperly delivered to the target site.
 67. A method according to claim64, wherein said at least two data sets correspond with a hyperpolarized¹²⁹Xe gas NMR signal data acquisition obtained both before saiddelivering step and after said delivering step.
 68. A method accordingto claim 65, further comprising at least one of adjusting the quantityor formulation of the drug and confirming the proper delivery to thetarget site.
 69. A method according to claim 64, wherein the treatmentcondition is one of cancer, cardiac, renal, hepatic or pulmonaryfunction, and cerebral function, and wherein the target site is selectedso as to administer polarized ¹²⁹Xe gas to a region representative ofthat condition.
 70. A method of determining the presence of canceroustissue, comprising the steps of: delivering a quantity of apharmaceutical drug in vivo into a mammalian subject having a targetsite associated with a suspect mass or tissue abnormality; injecting aquantity of gaseous hyperpolarized ¹²⁹Xe in vivo into a mammaliansubject such that the hyperpolarized gas is delivered to the targetsite; generating a NMR image or spectroscopic signal of the target sitecorresponding to the injected hyperpolarized ¹²⁹Xe gas; and evaluatingthe NMR image or signal for the presence or absence of signaturepatterns in the generated image or signal associated with the presenceor absence of cancer.
 71. A method according to claim 70, wherein thesuspect mass is a solid mass in the breast and said evaluating stepdetermines in vivo the presence or absence of breast cancer.
 72. Aninjectable ¹²⁹Xe gas product, said ¹²⁹Xe gas product formulated as asterile non-toxic hyperpolarized gas formulation which consistsessentially of isotopically enriched ¹²⁹Xe in gaseous phase which isinjected in vivo in a quantity of less than about 20 cubic centimeters.73. An injectable ¹²⁹Xe gas pharmaceutical grade product, said productformulated as a sterile non-toxic product which consists essentially of¹²⁹Xe in gaseous phase and traces of CO₂, wherein said injectable gasproduct is configured to be dispensed in vivo.
 74. An syringe,comprising: a primary gas holding chamber having inner and outersurfaces; a plunger sized and configured to be received within saidprimary gas holding chamber, wherein said plunger has a gas contactingsurface; a quantity of hyperpolarized noble gas held in said primary gasholding chamber; a valve member operably associated with said primarygas holding chamber; and a capillary stem positioned intermediate ofsaid plunger and said valve member in fluid communication with saidprimary gas holding chamber wherein said primary gas holding chamberincludes a wall having outer and inner surfaces, and wherein saidprimary gas holding chamber inner surface and said plunger gascontacting surface are formed from a material which inhibits contactinduced polarization decay associated therewith.
 75. A syringe accordingto claim 74, further comprising an NMR excitation coil positionedproximate to said gas holding chamber such that in operation it excitesthe hyperpolarized gas held within said syringe.
 76. A syringe accordingto claim 74, in combination with a length of conduit and a catheter,wherein said conduit is operably associated with said valve and saidcatheter is configured to be attached to a subject.
 77. A syringe andcatheter combination according to claim 76, wherein said conduit hasopposing first and second end portions such that said second end portionis proximate to said syringe gas holding chamber and said first endportion is operably associated with a lumen configured for insertionalengagement into the vasculature of a subject to deliver said quantity ofhyperpolarized gas thereto.
 78. A syringe and catheter combinationaccording to claim 76, wherein syringe and catheter are operablyassociated with a delivery path which is configured to form bubbles withdiameters which are less than about 150 microns.
 79. A method accordingto claim 74, wherein said delivery path is configured to form polarized¹²⁹Xe gas bubbles with diameters which are less than about 10 μm.
 80. Amethod of preparing a gas container having a sealable gas holdingchamber prior to the introduction of a polarized product therein,comprising the steps of: (a) evacuating the gas container; (b)introducing a quantity of CO₂ gas therein; and (c) repeating step (a)after step (b).
 81. A method of sizing the length of a capillary stem ona container having a primary hyperpolarized gas holding chamber with avolume, the capillary stem having a volume which is substantially lessthan that of the gas holding chamber and includes a wall defining a flowchannel aperture having a radius or width and a length, the wall havinga gas contacting surface formed of a material having a relaxivity valuefor a selected hyperpolarized gas associated therewith, the methodcomprising the steps of: defining a capillary stem aperture size;determining the type of hyperpolarized gas to be held in the containerand a diffusion coefficient associated therewith; establishing arelaxivity value for the material forming the capillary wall; andcalculating an optimal capillary stem length.
 82. A container having aprimary gas holding chamber with a capillary stem, said capillary stemhaving a length defined by the method of claim
 81. 83. A container,comprising: a primary gas holding chamber having a primary volumeassociated therewith; a capillary stem having a wall with a gascontacting surface, a flow aperture, a length, and a capillary volume,said capillary stem in fluid communication with said gas holdingchamber, wherein said gas contacting surface of said wall has arelaxivity value for a selected hyperpolarized gas associated therewith;and a quantity of hyperpolarized gas held in said gas holding chamber;wherein said capillary stem length is selected to substantiallycorrespond to an optimal length to improve the polarization life of thehyperpolarized gas held therein, and wherein the optimal length iscalculated based on a desired T₁, the width of the capillary flowaperture, and the relaxivity value.
 84. A container according to claim83, wherein said primary chamber volume is about 20cm³, said capillarystem width is about 1 mm, said quantity of hyperpolarized gas comprises¹²⁹Xe and said capillary stem length is about 4.4 cm.
 85. A containeraccording to claim 83, wherein said container has a capillary stemlength which is longer when said gas is ³He than when said gas is ¹²⁹Xe.86. An injection system for administering polarized gas to a subject,comprising: a polarized noble gas supply; a catheter configured andsized for intravenous or intrarterial placement in a subject in fluidcommunication with the supply of polarized noble gas; and an injectionhead positioned in a distal portion of the catheter, wherein saidinjection head comprises multiple orifices having a width of betweenabout 1 nm-50 μm, configured so that, in operation, hyperpolarized gasflows therethrough and out of the catheter into the subject.
 87. Aninjection system according to claim 86, wherein said injection headorifices are sized with a width between about 0.01-10 μm.
 88. Aninjection system according to claim 87, wherein said system furthercomprises an emulsifier source and a mixing chamber positionedintermediate said orifices and said emulsifier and polarized gassources.